The role of inflammasomes in vascular cognitive impairment

Poh, Luting; Sim, Wei Liang; Jo, Dong-Gyu; Dinh, Quynh Nhu; Drummond, Grant R.; Sobey, Christopher G.; Chen, Christopher Li-Hsian; Lai, Mitchell K. P.; Fann, David Y.; Arumugam, Thiruma V.

doi:10.1186/s13024-021-00506-8

Review
Open access
Published: 09 January 2022

The role of inflammasomes in vascular cognitive impairment

Luting Poh¹,
Wei Liang Sim¹,
Dong-Gyu Jo²,
Quynh Nhu Dinh³,
Grant R. Drummond³,
Christopher G. Sobey³,
Christopher Li-Hsian Chen^4,5,
Mitchell K. P. Lai⁴,
David Y. Fann^1,6,7,8 &
…
Thiruma V. Arumugam ORCID: orcid.org/0000-0002-3377-0939^2,3

Molecular Neurodegeneration volume 17, Article number: 4 (2022) Cite this article

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Abstract

There is an increasing prevalence of Vascular Cognitive Impairment (VCI) worldwide, and several studies have suggested that Chronic Cerebral Hypoperfusion (CCH) plays a critical role in disease onset and progression. However, there is a limited understanding of the underlying pathophysiology of VCI, especially in relation to CCH. Neuroinflammation is a significant contributor in the progression of VCI as increased systemic levels of the proinflammatory cytokine interleukin-1β (IL-1β) has been extensively reported in VCI patients. Recently it has been established that CCH can activate the inflammasome signaling pathways, involving NLRP3 and AIM2 inflammasomes that critically regulate IL-1β production. Given that neuroinflammation is an early event in VCI, it is important that we understand its molecular and cellular mechanisms to enable development of disease-modifying treatments to reduce the structural brain damage and cognitive deficits that are observed clinically in the elderly. Hence, this review aims to provide a comprehensive insight into the molecular and cellular mechanisms involved in the pathogenesis of CCH-induced inflammasome signaling in VCI.

Dementia: a focus on vascular cognitive impairment

Dementia describes a set of symptoms that occur when the brain is damaged by injury or disease. These commonly include progressive deterioration in memory, thinking and behavior, and ultimately the ability to perform everyday activities [1]. Dementia can be caused by many neurological disorders including Alzheimer’s disease (AD), frontotemporal dementia, Lewy body dementia and vascular dementia (VaD). An estimated 35.6 million people worldwide were diagnosed with dementia in 2010, with these numbers expected to double every 20 years [2]. In particular, the proportion of VaD patients among the entire dementia population is reported to be approximately 15–20% in North America and Europe [3, 4], and 30% in Asia and developing countries [5,6,7].

In recent decades, increasing evidence has shown vascular diseases contributing to cognitive impairment and memory deficits, with an underlying vascular component in the etiology of most forms of dementia [8, 9]. Several studies have shown that with the inclusion of dementia arising from mixed neuropathologies, the percentage of the demented population with a contributing vascular cause may be up to 70% [10, 11]. To effectively target cognitive impairment due to vascular injury or diseases, the term Vascular Cognitive Impairment (VCI) was introduced to encapsulate the whole spectrum of disease, ranging from subjective cognitive impairment, mild cognitive impairment to dementia associated with underlying cerebrovascular disease burden [12, 13].

VCI arises from heterogeneous cerebrovascular pathologies with diverse vascular etiologies. From the perspective of vascular injury, the origin and type of vascular occlusion, hemorrhage, distribution of arterial territories, and vessel size are the common causes of the types of vascular pathologies due to large vessel diseases, small vessel diseases, ischemic-hypoperfusive and hemorrhagic diseases [14]. The underlying vascular etiologies for VCI have been extensively reviewed in the statement released by the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) [15].

Chronic Cerebral Hypoperfusion (CCH): a primary driver of VCI

Pre-clinical vascular diseases are difficult to detect until vascular lesions are formed and affect cognitive functions [16]. While numerous lines of evidence have identified risk factors associated with pre-clinical vascular diseases and VCI, the mechanisms by which these risk factors contribute to VCI pathologies resulting in cognitive impairment remain to be fully established [17,18,19]. Emerging evidence suggests that chronic cerebral hypoperfusion (CCH), as a result of vascular disease, could play a critical role in the pathophysiology of VCI [20,21,22]. CCH refers to a condition whereby cerebral blood flow (CBF) supply to the brain is reduced by 20 to 40% over a prolonged period. It can occur either to the whole brain or within specific brain regions [23, 24]. CCH is involved in the development of VCI as it is closely-associated with a number of major physiological vascular risk factors, VCI pathologies and cognitive decline [20, 25, 26]. It is well established CCH precedes white matter lesion (WML) formation and the presence of cerebral hypoperfusion together with white matter lesions, further exacerbates the decline in executive function and memory in VCI patients with dementia [27, 28].

Understanding the effect of CCH on cerebral function may explain its role in VCI. A continuous CBF plays an essential role in maintaining the brain’s structural and functional integrity [29]. At the neurovascular level, continuous blood supply to the brain parenchyma is necessary for essential functions such as neuronal activity, blood-brain barrier function and immune cell surveillance [8]. Disruption of blood flow to the brain is associated with a number of neurovascular dysfunctions such as endothelial dysfunction, glial activation, demyelination and blood-brain barrier breakdown as observed in VCI patients [30,31,32]. These observations warrant mechanistic investigations of VCI pathogenesis from the perspective of CCH. Various animal models have been developed to mimic a state of cerebral hypoperfusion as observed in VCI patients [33, 34]. By experimentally inducing CCH, these animal models provide a useful platform for understanding the underlying pathophysiology of VCI.

Pathogenic molecular mechanisms of CCH

Disruptions to CBF directly results in reduced glucose and oxygen supply, leading to immediate bioenergetic impairment and ionic imbalance, and development of excitotoxicity, oxidative stress and inflammation (Fig. 1).

Bioenergetic impairment and ionic imbalance

Bioenergetic impairment refers to the disruption of cellular energy metabolism. Inadequate blood supply due to CCH is likely to result in bioenergetic impairments as neurons are unable to produce sufficient adenosine triphosphate (ATP) for normal cellular functions [35, 36]. Reduction in ATP production leads to compromised function of ATP-dependent ion channels such as the Na⁺/K⁺ and Ca²⁺ pump. The ion channels’ inability to maintain an ionic balance results in a net Na⁺ and Ca²⁺ influx, and K⁺ efflux across the plasma membrane. Consequently, this increases the resting membrane potential to threshold, leading to unregulated depolarizations known as anoxic depolarization in neurons [37, 38].

Studies have provided evidence suggesting bioenergetic impairment and ionic imbalance caused by CCH [39,40,41]. Mitochondrial dysfunction has been reported to be evident in VCI, whereby the expression and activity of mitochondrial enzymes that are vital for ATP production and cellular bioenergetics are reduced in a CCH rodent model of VCI [39]. Several energy metabolites including ATP were significantly reduced upon CCH [40]. Impairment in Na⁺/K⁺ homeostasis has also been observed with CCH, with reduced blood flow leading to increased intracellular Na⁺ concentration and decreased in intracellular K⁺ concentration [35]. Pharmacological inhibition of Ca²⁺ influx offers neuroprotective effects on hippocampal neurons under CCH, demonstrating the significance of Ca²⁺ influx in mediating CCH-induced injuries [42].

Excitotoxicity

Excitotoxicity is the damage or death of neurons from the uncontrolled stimulation of excitatory glutamate receptors and is prevalent during CCH. As neurons undergo anoxic depolarization during cerebral hypoperfusion, there is a resulting influx of Ca²⁺ ions into the presynaptic neuronal terminals, culminating in a massive release of the excitatory neurotransmitter glutamate into the synaptic cleft [35, 43]. Consequently, postsynaptic glutamate receptors on surrounding neurons become overstimulated, causing a large influx of Na⁺ and Ca²⁺ ions that trigger the propagation of an uncontrolled downstream cytotoxic cascade. Accumulation of intracellular Na⁺ creates an osmotic pressure for water to enter the neuron, leading to cytotoxic swelling and lysis [35, 44, 45]. High levels of intracellular Ca²⁺ activate downstream catabolic enzymes such as endonuclease and calpain, which degrade key cellular components such as nuclear DNA and the extracellular matrix, respectively, potentially resulting in either apoptosis and necrosis depending on CCH severity [38, 46]. Studies have shown the therapeutic potential of interventions targeting excitotoxicity, including memantine, glutamate receptor antagonist and calcium channel blockers, in ameliorating VCI for both patients and rodent models of VaD [47,48,49,50].

Oxidative stress

Oxidative stress occurs when the balance of reactive oxygen species (ROS) and antioxidants disrupted and is increasingly implicated in VaD. Upon disruption of CBF, the mitochondrial electron transport chain is disturbed, electron leakage occurs and reaction with oxygen produces a ROS called superoxide (O₂⁻) [38, 51, 52]. Disruption of calcium homeostasis during CCH-induced excitotoxicity can also trigger ROS overproduction through depolarization of the mitochondrial membrane and activation of downstream ROS-generating enzymes such as NADPH (nicotinamide adenine dinucleotide phosphate) oxidases and xanthine oxidase [53, 54]. It was recently suggested that a major source of ROS production in the cytosol was activated NADPH oxidase in VCI, with enzyme inhibition capable of ameliorating cognitive impairment in a CCH rodent model [55]. Moreover, O₂⁻ can spontaneously undergo a series of dismutation reactions to form other types of ROS such as hydrogen peroxide (H₂O₂) and hydroxyl radical (OH⁻) [56, 57].

Oxidative stress can cause DNA damage and induce oxidation of lipids and proteins that eventually results in apoptotic death [58]. Elevated hydrogen peroxide levels were observed in isolated mitochondria from the brain of rodent models of VCI, with an increase proportionate to the duration of CCH [39]. Several markers of oxidative stress are elevated in VCI patients, such as lipid peroxidation and oxidized DNA, coupled with reduced antioxidant levels in the plasma [59,60,61].

Neuroinflammation

Neuroinflammation is characterized by an increased production of proinflammatory cytokines and chemokines by resident brain cells such as microglia and astrocytes, together with infiltration of peripheral immune cells into the CNS [62, 63]. This is usually in response to pathogens or to a variety of pathophysiological mechanisms such as bioenergetic imbalance, excitotoxity, mitochondrial dysfunction and oxidative stress causing stress or injury to neurons, glial and vascular endothelial cells during CCH. Consequently, danger signals such as damage-associated molecular patterns (DAMPs) that are released into the extracellular environment are able to initiate local and systemic inflammation [62, 63].

The presence of chronic inflammation has been reported in VCI patients during pre-clinical, clinical and severe stages of VaD [64,65,66,67]. These studies reported elevated levels of classic inflammatory mediators such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), TNFα and C-reactive protein (CRP) that propagate inflammation, leading to degradation of the tissue matrix and infiltration of peripheral immune cells causing various forms of cell death [64,65,66,67]. Studies in animal models suggest that CCH can induce both acute and chronic neuroinflammation that damage the myelin sheath, blood-brain barrier (BBB) and grey matter via oligodendrocyte loss, endothelial cell dysfunction, and apoptotic and necrotic cell death of the neurovascular unit [68,69,70,71]. Furthermore, the complement system may also be involved in driving late stage neuroinflammatory processes via complement factor 5a (C5a), as elimination of C5a in a VCI mouse model exerts a protective effect against CCH-induced injury [72].

Pathogenic cellular mechanisms of CCH

The aforementioned molecular mechanisms initiated by CCH are critical drivers of subsequent pathogenic cellular mechanisms in VCI such as glial activation, blood-brain barrier dysfunction, cell death and demyelination (Fig. 1).

Glial activation

Glial activation occurs when resident immune cells switch from a resting state to an activated state to initiate a series of changes in glial function following cellular stress and injury in the brain. In general, microglia and astrocytes are considered the main resident immune-associated cell types in the brain that respond readily to microenvironmental disturbances. CCH can trigger glial activation through ionic imbalance, oxidative stress and neuroinflammation [23, 73, 74] .

Several studies of brains from VCI have shown the presence of reactive astrocytes and microglia in the areas surrounding lesions, alongside markers of oxidative stress and inflammation [75,76,77]. These activated glial cells are likely to be involved in the pathophysiology of VCI via several mechanisms. Firstly, they initiate and facilitate neuroinflammation, leading to cellular injury and leukocyte infiltration into the brain [78, 79]. Secondly, inflammation suppresses the pro-survival action of endothelial cells on neurons by reducing neurotrophic signaling leading to endothelial cell atrophy and microvascular rarefaction [80, 81]. Thirdly, activated microglia release proinflammatory cytokines and chemokines that disrupt BBB integrity by redistributing tight junction proteins and reorganizing the actin cytoskeleton in microvascular endothelial cells in the brain [82, 83]. Finally, glial activation contributes to demyelination by impeding remyelination, as reactive astrocytes and microglia surrounding the white matter lesion release IL-1β and hyaluronan to inhibit maturation of oligodendrocytes during CCH [69, 84].

Blood-Brain barrier dysfunction and breakdown

Blood-brain barrier (BBB) dysfunction is when the integrity of the highly selective semipermeable border surrounding the brain parenchyma is compromised. BBB function involves coordinated interactions between endothelial cells and pericytes regulating the selective diffusion of substances into the brain parenchyma. In particular, it is regulated by tight junction proteins (TJPs) located between endothelial cells, with the support of pericytes attached [85, 86]. Disruption of TJP arrangement or distribution loosens the interaction between adjacent endothelial cells, compromising the physical barrier and increasing its permeability to foreign substances [87, 88]. CCH-induced oxidative stress and inflammation contribute significantly to BBB dysfunction by reducing the density of TJPs on the endothelial membrane [89,90,91]. Inflammation can also upregulate cell adhesion molecules (i.e. Intercellular Adhesion Molecule (ICAM) and Vascular Cell Adhesion Molecule (VCAM) to facilitate the infiltration of peripheral immune cells across the BBB to release additional ROS and proinflammatory cytokines [90, 92, 93]. Finally, proinflammatory cytokines can upregulate gene expression of matrix metalloproteinases, MMP2 and MMP9, that can also degrade the extracellular matrix contributing to BBB dysfunction [94, 95].

Dysfunction of the BBB is increasingly implicated in VCI [96, 97]. In multiple mouse models of CCH, impairment of the BBB is observed through increased vascular permeability of intravascular Evans blue dye and horseradish peroxidase (HRP) into the brain parenchyma [91, 98, 99]. Several studies have also shown that CCH reduced pericyte coverage on capillaries, contributing to BBB dysfunction via endothelial transcytosis [91, 100, 101]. Moreover, the cerebrospinal fluid/plasma albumin ratio, another indicator of BBB damage, has also been reported to be elevated in VCI patients relative to healthy controls, with the severity of BBB damage corresponding to white matter lesions [102]. While the nature and extent of BBB disruption in the pathogenesis of VCI remains to be fully elucidated, it is currently thought to be mediated by oxidative stress and neuroinflammation [103, 104].

Cell death: necrosis and apoptosis

The aforementioned pathogenic molecular mechanisms caused by CCH, including bioenergetic imbalance, excitotoxicity, oxidative stress and inflammation, can disrupt the integrity of the neurovascular unit leading to programmed neuronal and glial death [38, 58, 105]. In particular, accumulation of Ca²⁺ in the cytosol from excitotoxicity can activate catabolic enzymes that cleave DNA and hydrolyze cellular cytoskeletal proteins to cause apoptosis [46, 106, 107]. Similarly, CCH-induced oxidative stress and neuroinflammation can also activate cell death pathways. For example, H₂O₂ can trigger necrosis and apoptosis via the modulation of activator protein-1 (AP-1) and B-cell lymphoma-2 (Bcl-2) family proteins, respectively [108, 109]. The proinflammatory cytokine, TNF-α, is a critical ligand for death receptors that can activate pro-apoptotic caspase-8 and -3 in the extrinsic apoptotic pathway during CCH [110].

Necrosis and apoptosis are two types of cell death that have been established to occur clinically in VCI. In VCI, necrotic cell death can be observed within lacunar infarcts formed when the brain tissue is exposed to total or partial reduction of blood flow [111, 112]. Apoptosis is a highly conserved cell death pathway involving the family of cysteine-dependent aspartate specific proteases (Caspases), which induces DNA fragmentation and phagocytic signaling [113, 114]. Apoptosis has also been observed in cerebral autosomal dominant arteriopathy with CADASIL patients and various mouse models of VCI [115,116,117]. In addition to necrosis and apoptosis, recent studies have demonstrated inflammasome mediated necroptotic and pyroptotic forms of cell death during CCH, suggesting its potential involvement in VCI [66, 71, 118, 119].

Demyelination

Demyelination refers to a condition where the protective myelin sheath that surrounds neuronal axons is damaged and degraded. It is commonly observed within the deep white matter in patients with small vessel disease, leading to cognitive decline in the aged brain [120, 121].

CCH can result in demyelination induced by a hypoxic-ischemic environment and inflammation [121, 122]. Hypoxic conditions trigger the activation of the hypoxia-inducible factor-1 (HIF-1) regulatory pathway leading to inflammation and apoptotic cell death [76, 123]. Inflammation activates glial cells to release inflammatory mediators such as TNF-α, matrix metalloproteinases (MMPs) and serine proteases that damage the myelin sheath [77, 124, 125]. Active proteases (i.e. MMP-1, MMP-2, MMP-3, MMP-7, MMP-9 and Calpain) induced by CBF disruption degrade myelin basic protein (MPB), and disrupt the polymeric network within the myelin sheath [95, 124, 126]. Moreover, CCH-induced inflammation can initiate activation of apoptosis and pyroptosis in oligodendrocytes, that may attenuate myelin synthesis and repair, and exacerbate demyelination [71].

Pathological Structural features and cognitive impairment from CCH

Several structural pathological features are observed in the brain during VCI. Advances in neuroimaging have allowed detection of white matter lesions, lacunes, microinfarcts, microbleeds and enlarged periventricular spaces, which are now considered standard diagnostic features of VCI [15, 127, 128]. In this section, several key pathogenic structural damages and cognitive impairment associated with CCH will be discussed (Fig. 1).

White matter Lesions

White matter lesions (WMLs) are regions in the brain parenchyma with demyelination in the white matter that appear as hyperintensities (without cavitation) on T2-weighted MRI images [128]. WMLs are primarily formed from axonal demyelination that is usually produced from the loss of oligodendrocytes [129, 130], and accompanied by both glial activation [131, 132] and loss of axon-glial integrity [133]. These features are a reflection of the underlying mechanisms of CCH-induced WML formation. As discussed above, CCH triggers molecular mechanisms that contribute to glial activation, cell death and demyelination. As cerebral hypoperfusion persists, these injuries accumulate at the cellular level, especially in oligodendrocytes within the white matter region and surrounding glial cells.

WMLs are a significant contributor to cognitive decline and are a prominent feature of VCI [134,135,136]. WMLs disrupt the functional connections between the cortical and subcortical regions, affecting cognitive function and emotions [137, 138]. WMLs also reflect loss of cholinergic neurons, compromising the neurotransmitter system, eventually leading to cognitive decline in VCI patients [134, 139]. The main mechanisms underlying the formation of WMLs in humans are critical stenosis and hypoperfusion of medullary arterioles in small vessel disease (i.e. arteriolosclerosis) and hypotensive episodes [140,141,142]. White matter regions with lower CBF developed into WMLs in a longitudinal study [143]. The positive association between CCH and a decline in cognitive function is particularly profound in patients with severe WMLs [28]. In mouse models, CCH resulted in similar white matter rarefaction and lesion formation together with cognitive impairment, further emphasizing the common role of WMLs in VCI [71].

Microinfarcts

Microinfarcts are small fluid-filled spaces/lesions that appear in large numbers within the cortical and subcortical brain regions. The formation of microinfarcts is usually caused by the activation of necrotic and programmed cell death pathways in neurons and glial cells, and commonly associated with neuronal loss, gliosis and axonal damage [144,145,146]. This process is often accompanied by the migration of glial and peripheral immune cells, such as macrophages, to the necrotic site of injury. Immune cells phagocytose damaged cells, and astrocytes proliferate and undergo gliosis to form a barrier around the lesion to limit the spread of necrosis [145,146,147].

Microinfarcts are more prominent in VCI than in other demented patients [148]. In VCI, microinfarcts are associated with cerebral amyloid angiopathy and reduced cerebral perfusion [22, 120]. Several post-mortem studies have demonstrated that hypoperfusion initiates and promotes the progression of microinfarct formation in brain areas vulnerable to hypoperfusion (i.e. watershed cortical region) [149, 150]. Microinfarcts affect the brain structural network, leading to impaired performance in various cognitive domains [151, 152]. Microinfarcts also cause primary disruption to local tissue function, secondary inflammation and axonal disorganization to the white matter tracts, further exacerbating damage to brain circuits and function [153,154,155].

Hippocampal atrophy

Hippocampal atrophy refers to the loss of neurons and neuronal volume in the hippocampus. It is a classic marker for AD, but can also be observed in VCI patients. The degree of atrophy has been estimated to be 16.6% in AD and 11.6% in VCI [156,157,158]. The hippocampus is a complex brain region that is highly sensitive and vulnerable to insults caused by reduced cerebral perfusion or hypoxia, which stimulate a number of pathogenic mechanisms such as excitotoxicity, oxidative stress, and inflammation to activate cell death pathways [159, 160], leading to hippocampal atrophy. Animal studies have shown that with CCH, the hippocampus displays acute neuronal damage and cell death originating from the CA4 area, to CA2 and CA3, with the CA1 area being the last zone affected [71, 161, 162]. Decline in memory performance, spatial navigation and visuospatial functions have been observed in patients with hippocampal atrophy [163, 164]. While the direct mechanistic explanation for these associations in VCI has not been established, it is suggested that reduced neuronal capacity in the hippocampal area lowers its connectivity with other brain regions [163,164,165]. Decreased levels of the synaptic protein synaptophysin has been reported in VCI patients compared to healthy subjects, suggesting a potential deficit in synaptic transmission upon hippocampal atrophy [144, 166] .

Cognitive dysfunction in VCI

VCI encompasses a broad spectrum of cognitive dysfunctions ranging from subjective cognitive impairment, mild cognitive impairment to dementia (VaD) [8, 13]. The underlying pathophysiological mechanisms responsible for CCH-induced cognitive impairment may be extensive and severe. CCH initiates several cellular mechanisms - glial activation, BBB dysfunction, cell death and demyelination, via the activation of numerous pathogenic molecular mechanisms, including bioenergetic impairment and ionic imbalance, excitotoxicity, oxidative stress and neuroinflammation in different types of brain cells. These mechanisms all contribute to structural damage such as WMLs, microinfarcts and hippocampal atrophy. The influence of these structural damages on cognitive function was discussed previously.

Several guidelines have proposed that VCI is a syndrome with evidence of either clinical stroke or subclinical vascular brain injury, and cognitive impairment affecting at least one cognitive domain [8, 15, 167]. The cognitive domains involved in diagnosing VCI are executive/attention, memory, language, and visuospatial function [8]. Executive dysfunction is a well characterized neurological feature of VaD and can be present in VCI patients who are not demented [168, 169]. Impairments to executive functions are heavily associated with lesions and damage within the frontal lobes or downstream frontal-subcortical circuits of VCI/VaD patients [170, 171]. Memory impairment is a key feature of AD and is also important in VaD. Studies have shown that VaD patients experienced greater impairment in semantic memory than AD patients, possibly due to the inability to retrieve information from short and long-term memory [172,173,174]. Impairments in language and visuospatial functions can also be observed in VCI. When presented with a picture description task, VaD patients exhibit lower semantic content production while maintaining a fluency comparable to healthy patients [175]. VaD patients show impairments in most of the tests associated with visuospatial tasks, indicating a deficit in constructional and visuoperceptual ability [174, 176].

Inflammation – a critical molecular mechanism and a bridge between CCH and various cellular mechanisms

Several key events have been identified in the pathophysiology of VCI, as briefly summarized above. However, whether these events are causative or merely consequential to the progression of VCI has yet to be conclusively validated. A comprehensive understanding on the pathogenesis of VCI will not only pave the way for development of interventions, but allow us to target VCI with maximum efficacy [8]. In addition, interventions targeting an early temporal event in the pathogenesis of VCI would better attenuate other repercussions elicited by the many late temporal events in the pathogenesis of VCI. Hence, there is an increasing focus on exploring the temporal profile of events in the pathogenesis of VCI. The current notion regarding VCI remains that the underlying root cause is the initial disruption to CBF, with a cascade of events leading to cognitive impairments [20,21,22, 26, 177]. Specifically, several lines of evidence have highlighted a plausible causative role of neuroinflammation as an early temporal event that then influences other mechanisms in contributing to the pathogenesis of VCI [64,65,66,67, 77].

Neuroinflammation has been implicated in dementia, and is associated with a decline in cognitive functions and functional connectivity in demented patients [178, 179]. Elevated levels of inflammatory markers, including the highly sensitive CRP and IL-6, IL-8 and IL-1β, were found in brain tissues and peripheral samples of demented patients [65, 66, 180,181,182]. Some of them (e.g. IL-6 and CRP) were even associated with an increased risk of dementia, including VaD [181, 182]. However, a few studies demonstrated lower levels of inflammatory mediators in patients with dementia. For example, Chen et al. and Mulugeta et al. showed that normal controls had significantly higher levels of IL-6 and IL-8 in different parts of the brain when compared to AD, mixed dementia or VaD patients [183, 184]. It was also observed that IL-6 and IL-8 levels were lower in the cerebrospinal fluid and plasma of patients with AD [185, 186]. While the results are controversial, it is essential to consider the following points. Firstly, the profile of cytokines may depend on the stage and progression of the disease [187, 188]. Secondly, some of these inflammatory cytokines, such as IL-6 and TNF-α, may exhibit pleiotropic actions with known pro- or anti-inflammatory effects [187, 188], which adds more complexity to the interpretation of these studies. Lastly, heterogeneity of post-mortem samples and difficult application of the detection methods for proinflammatory mediators in the brain and peripheral samples may account for the contradictory conclusions of some studies [189,190,191]. Despite these variable results, inflammation is still considered one of the critical underlying mechanisms of dementia. More importantly, the levels of these proinflammatory mediators were shown to be elevated even before the clinical onset of VaD [67] suggesting that neuroinflammation may be involved in both early and late stages of VCI disease progression.

The associations between neuroinflammation and impairments in cognitive function may stem from its involvement in several key events in the pathogenesis of VCI, such as glial activation, BBB dysfunction, cell death, demyelination and WML formation. The influence of neuroinflammation on these events through the action of the inflammasome signaling pathway will be discussed in the following section.

Inflammasome signaling pathway: linking IL-1 to VCI

Among the numerous inflammatory mediators implicated in VCI, one group of proinflammatory cytokines is prominent: the interleukin-1 (IL-1) family. Amongst the IL-1 family members, both IL-1β and IL-18 are increasingly implicated in the progression of VCI. Elevated levels of both IL-1β and IL-18 have been reported in the serum of VaD patients [64, 65, 192]. While there could be an involvement of systemic inflammation in the studies of serum samples, post-mortem studies of different brain tissues showed that the level of IL-1β was higher in the frontal cortex and hippocampus of VaD patients in comparison to controls [66, 193] indicating that IL-1β may be strongly involved in the process of neuroinflammation during VCI. The production and maturation of both IL-1β and IL-18 is primarily driven from a major arm of the innate immune system termed the inflammasome signaling pathway [194]. As such, this pathway is likely to serve as a critical point in regulating production of IL-1 family cytokines during the pathogenesis of VCI.

Overview of the Inflammasome signaling pathway

Inflammasomes are macromolecular protein complexes that are essential signaling platforms capable of detecting pathogenic signals via pathogen-associated molecular patterns (PAMPs) and endogenous sterile stressors via damage-associated molecular patterns (DAMPs) [38]. Upon detection of PAMPs or DAMPs, the inflammasome complex is activated to trigger downstream inflammatory cascades such as the production of inflammatory cytokines. Given its sterile nature, neuroinflammation in VCI can be considered exclusively driven by DAMPs. The two main characterized inflammasome signaling pathways are the canonical and non-canonical pathways, each of which involves two steps to achieve inflammasome signaling: priming and activation [38, 195, 196].

The canonical inflammasome signaling pathway typically leads to the activation of caspase-1 and -8 (Fig. 2). The priming step (i.e. Signal 1) is initiated by the presence of DAMPs (e.g. HMGB1, IL-1α), which can activate various extracellular PRRs including toll-like receptors (TLR; TLR2, TLR4), receptor for advanced glycation end-products (RAGE) and interleukin-1 receptor 1 (IL-1R1) [195, 197], leading to downstream activation of NF-κB, MAPK, p53 and JAK-STAT pathways [38, 195, 198]. The main purpose of priming is to increase gene expression of key inflammasome components (i.e. receptor/sensor, adaptor and effector) and precursors of IL-1β and IL-18 in the cytosol [199, 200]. Priming can be independent of transcriptional expression whereby post-translational modifications (i.e. phosphorylation and de-ubiquitination) are essential to “license” inflammasome activation [201]. The activation step (i.e. Signal 2) involves stimulation of cytosolic inflammasome receptors/sensors that can be triggered by various DAMPs and/or disturbances in the cellular microenvironment, resulting in assembly and activation of the canonical inflammasome complex to facilitate activation of effectors caspase-1 and -8 [194, 202]. The NLRP3 complex is arguably the best characterized inflammasome, and along with the NLRP1, NLRC4 and AIM2 inflammasome complexes facilitates the self-cleavage of total caspase-1 and -8 into biologically active cleaved caspase-1 and -8, respectively [194, 195, 203, 204]. Both cleaved caspase-1 and -8 can cleave precursors of both IL-1β and IL-18 into mature proinflammatory cytokines that can then amplify downstream inflammation [205, 206]. Cleaved caspase-1 and -8 are also implicated in the activation of programmed cell death pathways such apoptosis and pyroptosis [207,208,209], and will be discussed below.

The non-canonical inflammasome signaling pathway leads to the activation of the mouse homolog caspase-11, with the corresponding human homologs being caspase-4 and -5 (Fig. 2). It shares some similarities to the canonical activation of caspase-1, although the non-canonical pathway possesses some unique characteristics. Transcriptional priming is also present for caspase-11 in the non-canonical inflammasome signaling pathway, mediated by extracellular PRRs, including Toll-Like Receptors (TLRs) (i.e. TLR2, TLR4), RAGE and IL-1R1 [195, 197]. Total caspase-11 can detect cytosolic lipopolysaccharides (LPS) from gram-negative bacteria, and oligomerize to form a macromolecular complex of full length caspase-11 components. Subsequently, full length caspase-11 undergoes autoproteolytic cleavage via proximity-induced activation and conversion to its active cleaved form. Cleaved caspase-11 can induce pyroptosis and also indirect maturation of IL-1β and IL-18, in a caspase-1-dependent manner via induction of K⁺ efflux [210, 211]. Low intracellular K⁺ levels can activate NLRP1 and NLRP3 inflammasomes, thereby linking the non-canonical pathway to the canonical inflammasome pathway [212, 213]. Caspase-11 can also be activated by a class of DAMPs known as oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC), although oxPAPC upregulates the production and secretion of IL-1β, but does not induce pyroptosis [214].

Molecular structure of Inflammasome components

A canonical inflammasome complex is typically comprised of three distinct components: a receptor/sensor, an adapter and effector (Fig. 3). The sensor is usually a cytosolic PRR that detects perturbations in the intracellular microenvironment that serve as the activation signal to initiate inflammasome assembly. The inflammasome complexes are named after their respective intracellular PRR, which are from two major families: the nucleotide-binding oligomerization domain-like receptor (NLR) family and the pyrin and hematopoietic expression, interferon-inducible, nuclear localization (HIN) domain-containing (PYHIN) family [38, 194]. Members of the NLR family share similar structural domains such as the NLR apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1), collectively known as NACHT, and a leucine-rich repeat (LRR) [215, 216]. The NACHT domain is responsible for NLR oligomerization, while LRR is the inhibitory unit folded onto the NACHT domain, keeping the receptor in its inactive state. The two other critical domains are the Pyrin (PYD) domain and the caspase activation and recruitment domain (CARD), which interact with other components with similar domains to form the inflammasome complex [38, 194, 217, 218]. Molecular structures of the AIM2, NLRP1, NLRP3, and NAIP-NLRC4 receptor complexes are discussed below (Fig. 3).

The NLR-pyrin domain containing 1 (NLRP1) belongs to the NLR family of PRRs, with only a single variant of NLRP1 found in humans [194, 219]. The NLRP1 receptor consists of an N-terminal PYD, NACHT, LRR, function-to-find domain (FIIND) and a C-terminal CARD domain. The FIIND domain is unique to NLRP1 in the NLR family, and may play an autoinhibitory role [219, 220] (Fig. 3). The NLR-pyrin domain containing 3 (NLRP3) belongs to the NLR family of PRRs and is perhaps the most studied of all inflammasomes. The NLRP3 receptor consists of an N-terminal PYD, NACHT and LRR domain [194, 221] (Fig. 3). The NLR apoptosis inhibitory protein (NAIP) and the NLR-CARD containing 4 (NLRC4) belong to the NLR family as they both contain NACHT and LRR domains. NAIP is distinct from other NLR proteins as they contain three baculovirus inhibitor-of-apoptosis repeats (BIR) at the N-terminal domain. Unlike the previously mentioned PRRs of the NLR family, NLRC4 contains an N-terminal CARD rather than a PYD domain, in addition to the NACHT and LRR domains [194, 222] (Fig. 3). The absent in melanoma 2 (AIM2) belongs to the PYHIN family of PRRs, and together with four other members forms the AIM2-like receptor (ALR) family of inflammasomes. AIM2 is a bipartite protein, consisting of an N-terminal PYD and a 200-amino-acid HIN domain with two oligonucleotide/ oligosaccharide-binding folds [218, 223]. The HIN domain can bind to double-stranded DNA (dsDNA) independent of its sequence, and during the absence of ligand binding can interact in an intramolecular manner with the PYD to result in autoinhibition [218] (Fig. 3).

The adapter, known as apoptosis-associated speck-like protein containing a CARD (ASC), is a protein responsible for the interactions between various inflammasome components, such as a scaffold protein that connects the PRR to the effector components. ASC contains both an N-terminal PYD domain and a C-terminal CARD domain [217, 224] (Fig. 3).

The effector protein components are a group of inflammatory caspases that catalyze a broad spectrum of substrates upon activation. Caspase-1, − 8 and − 11 play a significant role as the effectors in the inflammasome signaling pathway. Both caspase-1 and -11 contain an N-terminal CARD domain and C-terminal catalytic domain (composed of large p20 and small p10 subunits). Caspase-8 contains two death effector domains (DED) at its N-terminal and the catalytic domain at the C-terminal [225, 226]. Although these caspases are similar in structure, they differ in their domain linkers and residues in their catalytic pocket, contributing to their differential role in the inflammasome signaling pathway [227,228,229] (Fig. 3).

Possible Inflammasome-inducing stimuli in VCI

During the pathogenesis of VCI, a multitude of stress signals and DAMPs are produced in the cytosol, released and detected by various PRRs, resulting in their eventual activation and formation of inflammasome complexes [194, 200]. This section discusses stimuli that potentially activate the NLRP1, NLRP3, NAIP-NLRC4 and AIM2 inflammasome receptors during CCH (Fig. 4).

The exact function of NLRP1 in innate immunity is not yet fully elucidated, but it is believed to be activated via autolytic proteolysis within the FIIND domain in response to severe bacterial infections [220]. NLRP1 levels are upregulated in ischemic conditions, and although the responsible activation signals are unclear, they are likely to be from aberrations in the cellular microenvironment such as depletion of intracellular ATP and reduction of intracellular K⁺ levels arising from K⁺ efflux during bioenergetic impairment [38, 212, 230]. The NLRP3 receptor can be activated by a multitude of intracellular signals including decreased K⁺, increased Ca²⁺ and oxidative stress during CCH [212, 231, 232]. Given that NLRP3 can respond to a diverse range of signals, it is likely to be responding to a common cellular event caused by these activators rather than directly to the activators themselves. Moreover, increased levels of hyaluronic acid was observed in the cerebrospinal fluid of VaD patients that appeared to serve as a potential NLRP3 stimuli [233].

While no study to date has directly investigated the effect of CCH to cause bioenergetic deficits, blood flow reduction during ischemia is known to induce K⁺ efflux [46, 234]. This is a possible mechanism by which CCH activates the NLRP inflammasome receptors. Lower cerebral blood flow reduces ATP production and impairs ATP-dependent transporters such as the Na⁺/K⁺-ATPase pump leading to K⁺ accumulation in the extracellular space during ischemia [46, 234]. Alternatively, ATP released by damaged cells can bind to the P2X purinoceptor 4 (P2X4) and P2X purinoceptor 7 (P2X7) on neighboring cells, leading to opening of the ligand-gated ion channel and K⁺ efflux. In addition, K⁺ can be passively released into the extracellular environment due to increased permeability of the plasma membrane from damaged cells [38, 235]. Elevated levels of extracellular K⁺ can activate Pannexin-1 channels on the plasma membrane through a mechanism independent of the membrane potential, to further promote release of ATP, creating a positive feedback loop for K⁺ efflux [38, 236, 237]. K⁺ efflux has been identified as a key step for NLRP1 and NLRP3 inflammasome activation, although there is no clear understanding of the precise mechanism linking K⁺ efflux and NLRP receptor activation [232, 238]. However, a recent study showed that low intracellular K⁺ concentrations can open the inactive structure of NLRP3 by altering a domain in between the PYD and NACHT domains, resulting in a stable structure that promotes the functional oligomerization of NLRP3 into active oligomers [239] (Fig. 4).

Other than K⁺ efflux, a reduced intracellular cyclic adenosine monophosphate (cAMP) concentration during CCH may activate the NLRP3 inflammasome [235, 240]. Binding of cAMP to the NLRP3 receptor inhibits its ability for inflammasome assembly. When cAMP is reduced upon CCH, NLRP3 activation is promoted [231, 235, 240]. While the underlying cause of cAMP reduction is unknown, evidence from mechanistic studies from ischemic models suggest an involvement of Ca²⁺. When Ca²⁺ is released by damaged cells, it activates G-protein coupled calcium-sensing receptors (CaSRs) on the plasma membrane, allowing it to interact with Gαi and inhibit adenylate cyclase, reducing the conversion of ATP to cAMP in neighboring cells [38, 231, 235]. The involvement of Ca²⁺ in mediating NLRP3 inflammasome activation is highly plausible as the Ca²⁺-permeable channel, transient receptor potential melastatin 2 (TRPM2), plays a significant role in regulating the production of IL-1β upon CCH [70]. One possible explanation for this is that it allows influx of Ca²⁺, which activates protein kinase R (PKR) in the cytoplasm. Upon activation, PKR can phosphorylate NLRP1 or NLRP3 receptors for inflammasome activation, leading to production of IL-1β [38, 241, 242] (Fig. 4).

Numerous lines of evidence have shown that NLRP3 inflammasome activation is closely linked to increased levels of ROS in neurological diseases [243, 244]. Several studies have already demonstrated a close association between ROS, thioredoxin-interacting protein (TXNIP) and NLRP3 [243,244,245]. The generation of ROS facilitates the uncoupling of TXNIP from thioredoxin (TRX), allowing TXNIP to bind to the NLRP3 receptor for inflammasome activation [244,245,246]. Due to increased oxidative stress observed in CCH mouse models of VCI [39, 55, 247], one study demonstrated that decreased TXNIP-associated oxidative stress was associated with reduced NLRP3 and IL-1β expression, in conjunction with better cognitive performance [248]. Another major source of ROS is from the mitochondria as increased hydrogen peroxide production induced oxidative stress that were observed in rodent models of CCH [39] (Fig. 4).

NAIP-NLRC4 is generally activated by pathogenic bacteria, with NAIP as a direct receptor to these bacterial signals [249] However, activation of NAIP-NLRC4 has been shown to be associated with lysophosphatidylcholine (LPC), which are lipids arising from the hydrolytic activity of phospholipase A2 (PLA₂) under stressed conditions [250, 251]. Although LPC has been found to activate NLRC4 and NLRP3 inflammasomes in neuroinflammatory disease mouse models [250, 252], it is unlikely to be involved in VCI as the levels of LPC do not differ significantly upon CCH [253]. Nucleotide-derived metabolites, including adenine and N4-acetylcytidine (N4A), can both prime and activate the NAIP-NLRC4 inflammasome [254], and could be relevant given that oxidative DNA damage has been described in VCI patients [60]. However, no evidence to date have investigated the effect of CCH on nucleotide-derived metabolites.

AIM2 is activated by the binding of dsDNA to the HIN domain, thereby removing the autoinhibitory effect of the intramolecular interaction between the PYD-HIN domains. This ligand binding is achieved via electrostatic attractions between the positively-charged HIN domain and negatively-charged dsDNA [218, 223, 255]. The dsDNA is required to be at least 80 base pairs in length and is conventionally from viral or bacterial origins [256]. Given the sterile nature of VCI, it is likely that AIM2 is activated by host dsDNA instead because ischemic conditions produce anoxic depolarization and release of mitochondrial DNA into the cytosol due to ATP-induced mitochondrial apoptosis. Coupled with the extracellular release of nuclear and mitochondrial DNA by injured neurons and glial cells, this provides the appropriate activation signals in the form of dsDNA to AIM2 [257, 258]. During CCH, DNA fragmentation has been observed to occur in astrocytes and oligodendrocytes [130, 259]. Furthermore, it was recently shown that CCH increases plasma levels of double-stranded DNA, and induces AIM2 inflammasome-mediated neuropathology and cognitive impairment in a mouse model of VaD [71]. Moreover, CCH-induced receptor for advanced glycation end-products (RAGE) upregulation can also promote DNA uptake into the cell via the action of endosomes, hence providing a mechanism through which extracellular DNA can interact with cytosolic AIM2 [260, 261] (Fig. 4).

Formation of the Inflammasome complex

In general, stimulation of the inflammasome receptor causes the LRR inhibitory unit to unfold from the NACHT domain [38, 216]. Consequently, the inflammasome receptor reconfigures into an “open” structure to allow homo-oligomerization with neighbouring inflammasome receptors. As more inflammasome receptors converge, they form a macro-molecular platform with their N-terminal PYD domains pointing towards each other [224, 262]. A PYD domain attracts other PYD domains via homotypic interactions. One of them is the adaptor protein, ASC, which facilitates inflammasome complex formation by binding to the PYD domain of the inflammasome receptor platform using its N-terminal PYD domain through homo-oligomerization [38, 224]. Many ASC proteins will come together during this process, forming a filamentous structure from the inflammasome receptor platform. These filamentous macromolecular aggregates are known as ASC specks [263]. As such, the CARD domain on the C-terminal of ASC is made available to bind with full-length caspases. These caspases bind with their N-terminal CARD domain to the ASC specks via CARD-CARD domain interactions [217, 263], and therefore directly interact with CARD domains on inflammasome receptors in the absence of the ASC adaptor. NLRP1 and NLRC4 receptors can mediate ASC-independent inflammasome activation [249, 264]. The structural formation of each major inflammasome complex is explained below (Fig. 5).

Following stimulation of the NLRP1 inflammasome receptor, the FIIND domain undergoes autolytic proteolysis to facilitate activation and oligomerization to form the inflammasome core [220]. NLRP1 oligomers appear to interact with ASC via homotypic PYD-PYD interactions [220]. After ASC speck formation, the ASC speck can recruit multiple effector inflammatory caspases via homotypic CARD-CARD interactions [219]. Despite being able to mediate ASC-independent NLRP1 inflammasome activation, NLRP1 activity level is higher in the presence of an ASC speck [220] (Fig. 5). Prior to NLRP3 activation, priming must occur in the form of increased expression and de-ubiquitination of NLRP3 [199, 201]. Assembly of the NLRP3 inflammasome also requires ASC to be linearly ubiquitinated [265]. The NLRP3 receptor binds to ASC via homotypic PYD-PYD interactions, and through the resulting ASC speck recruits effector inflammatory caspases via homotypic CARD-CARD interactions [221, 224] (Fig. 5). Upon binding of NAIP to the ligand, a single NAIP oligomerizes with multiple NLRC4 receptors. Phosphorylation of a single evolutionarily conserved serine 533 residue in NLRC4 is necessary for the assembly of the NAIP-NLRC4 inflammasome [266]. NAIP-NLRC4 then interacts with ASC likely through homotypic CARD-CARD interactions, given the absence of a PYD domain in the NAIP-NLRC4 receptor. ASC speck formation ensues and is accompanied by recruitment of multiple effector inflammatory caspases through homotypic CARD-CARD interactions. NLRC4, however, possesses an innate CARD domain, and so can recruit the effector inflammatory caspases independent of ASC, although the presence of ASC can enhance the assembly of the NAIP-NLRC4 inflammasome complex [222, 249, 263] (Fig. 5). The PYD domain of AIM2 possesses an intrinsic tendency to self-aggregate, resulting in homo-oligomerization of several AIM2 receptors after activation via dsDNA binding to the HIN domain. The AIM2 receptor complex then recruits ASC concomitant with ASC speck formation via homotypic PYD-PYD interactions. AIM2 recruits multiple effector inflammatory caspases via homotypic CARD-CARD interactions in an ASC-dependent manner, due to the absence of CARD in the AIM2 receptor [255, 267] (Fig. 5).

The molecular assembly of different inflammasome complexes can vary between inflammasome receptors in the canonical pathway. The ultimate purpose of inflammasome assembly is to bring together the effector caspases in close proximity. Increasing the local concentration of effector caspase-1 around the complex facilitates dimerization of caspase-1 monomers, and enables autoproteolytic activation [255, 267]. Subsequently, a transient activity hub of cleaved caspase-1 p33/p10 is produced for substrate catalysis. Different cell types and inflammasome sizes influence the kinetics of p33/p10 processing. Therefore, the final product of cleaved caspase-1 p20/p10 serves as a classic hallmark of caspase-1 activation as it indicates termination of protease activity [226, 268] (Figs. 2, 3 & 5). Unlike caspase-1, which binds to the inflammasome complex via CARD-CARD interactions, caspase-8 relies on its DED domain to carry out heterotypic interactions with the adaptor ASC. This is possibly due to the similarities with its self-association between DEDs and PYDs domains. As such, caspase-8 is similarly able to undergo proximity-induced activation, producing cleaved caspase-8 for substrate processing [224, 269, 270]. Nonetheless, caspase-8 is capable of cleaving inflammasome substrates (IL-1β) directly via the complex formation of caspase recruitment domain-containing protein-9 (CARD9), B-cell lymphoma/leukemia-10 (BCL10), Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), ASC and caspase-8. Caspase-8 can also interact with receptor-interacting serine/threonine kinase 1 (RIPK1) directly cleaving caspase-1 leading to caspase-1 activation [205, 206].

Organization of the canonical inflammasome complex usually involves a receptor, adaptor and effector caspases-1 and -8. However, in the non-canonical inflammasome pathway, caspase-11 can undergo homo-oligomerization in the absence of a receptor and adaptor protein component. Upon binding of a stimuli such as oxPAPC or LPS to the N-terminal CARD domain on caspase-11, the CARD domain interacts with the same domain on another caspase-11 to form a dimer [271, 272]. The dimer then interacts with others to form a homo-tetramer, which then oligomerizes to induces auto-proteolysis. As caspase-11 undergoes self-cleavage, it releases the pro-domain from the catalytic domain of caspase-11, producing biologically active cleaved caspase-11 [271, 272] (Figs. 2, 3 & 5).

Impact of the Inflammasome signaling pathway

Upon the activation of the inflammasome signaling pathway, the mature cytokines IL-1β and IL-18, are produced leading to the downstream inflammatory response. Simultaneously, these effector proteins also initiate a wide variety of cell death pathways such as apoptosis, pyroptosis and secondary necrosis [38] (Fig. 2).

Proinflammatory effect of IL-1β and IL-18

The proinflammatory cytokines, IL-1β and IL-18, are both transcriptionally upregulated during inflammasome priming [199]. They are produced in the form of precursor cytosolic proteins activated by canonical cleaved caspase-1 and -8, while cleaved caspase-11 aids in the release of these cytokines into the extracellular environment by inducing gasdermin pores [214, 268] (Fig. 2).

Following their production and release into the extracellular environment, mature IL-1β and IL-18 serve as ligands towards the IL-1R1 and IL-18R on the plasma membrane to facilitate an autocrine or paracrine effect. Consequently, this activates the NF-κB and MAPK(s) pathways to upregulate gene expression of several types of inflammatory mediators [38, 198, 273, 274]. The first type is proinflammatory cytokines (i.e. TNF, IL-1β, IL-6 and IL-8) that further propagate the inflammatory signal. The second is chemotactic cytokines (e.g. CXC-chemokine ligand 8 and CX3C-chemokine ligand 1), which attract peripheral immune cells such as neutrophils and macrophages to the damaged region. The third type is adhesion molecules (e.g. E-selectin and ICAM-1) that facilitate leukocyte infiltration into the brain parenchyma [275, 276]. These recruited peripheral immune cells can initiate a similar inflammatory response, and contribute to the pool of inflammatory mediators released from microglia and astrocytes [277, 278].

Effect of Caspase-1, − 8 and − 11 on cell death pathways

Apoptosis is a form of programmed cell death that encompasses the intrinsic and extrinsic apoptotic pathways. Activation of both pathways ultimately converge to activate executioner caspase-3, leading to apoptosis characterized by membrane blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, chromosomal DNA fragmentation and global mRNA decay [279, 280]. Inflammasomes induce apoptosis via recruitment and activation of caspase-8. Moreover, caspase-1 is also implicated in apoptosis through caspase-1 mediated cleavage of caspase-7 or caspase-3, both of which are involved in the execution of apoptosis [207, 281]. Caspase-11 can also activate caspase-3 to induce apoptosis in a caspase-1 independent manner [282]. Besides its apoptotic function, cleaved caspase-3 can induce secondary necrosis by cleaving the hallmark protein, gasdermin E to produce the N-terminal fragment (NT-GSDME). Secondary necrosis involves the oligomerization of these N-terminal fragments, leading to pore formation in the mitochondrial membrane and cellular surface [283] (Fig. 2), thus allowing cytochrome c to be released into the cytosol, further promoting apoptotic cell death [284].

Pyroptosis is an inflammasome-driven programmed cell death pathway that is initiated by the activation of caspase-1 and -11 resulting in cellular lysis [208, 210, 211]. Gasdermin D is an integral pyroptotic protein comprised of an N-terminal domain capable of forming a pore in the plasma membrane, and a C-terminal domain which represses the activity of the N-terminal gasdermin D domain (Fig. 2). Proteolytic cleavage of gasdermin D by either caspase-1 or − 11 relieves the inhibitory effect of the C-terminal gasdermin D domain on the N-terminal gasdermin D domain, allowing for translocation of N-terminal gasdermin D to the plasma membrane where it integrates and oligomerizes to form a gasdermin D pore [208, 210, 211]. Pore formation results in K⁺ efflux and influx of both Na⁺ and water molecules, resulting in cell swelling and lysis if there is a sufficient number of gasdermin D pores [208, 210, 211]. Pyroptosis is regarded as a proinflammatory form of cell death whereby proinflammatory cytokines such as IL-1β and IL-18 are usually restricted to the cytosol due to the lack of a secretory system but, along with other DAMPs and inflammatory mediators, they can be released into the extracellular environment after gasdermin pore formation [208, 210, 211]. Recently, caspase-8 was also demonstrated to cleave gasdermin D to induce pyroptosis [209]. In the absence of caspase-1 or gasdermin D, NAIP-NLRC4 can recruit and activate caspase-8 to induce a pyroptotic-like cell death involving the formation of membrane pores in a gasdermin D-independent manner [285].

Inflammasomes in Glial activation

As mentioned, microglia and astrocytes are key players in mediating neuroinflammation and tissue damage. Microglial cells are equipped with different PRRs that screen the microenvironment in the resting state [286, 287]. In an RNA-sequencing transcriptome study using mouse brain, gene expression of NLRP1, NLRP3, NLRC4 and AIM2 in the microglia was highest among all brain cell types. Moreover, microglial expression of caspase-1 and IL-1β was around four and thirty fold higher than neurons, respectively [288]. This primes microglia for rapid activation when CCH induces ionic imbalance, oxidative stress and inflammation. Canonical classification of activated microglia is broadly described as either proinflammatory M1-like or anti-inflammatory M2-like phenotypes. M1-polarised microglia produce proinflammatory cytokines such as IL-1β and TNF-α that serve to activate more microglia cells in a paracrine manner [289]. However, emerging transcriptomic studies revealed more disease-associated subtypes of microglia such as Keratan sulfate proteoglycan (KSPG)-microglia (associated with amyotrophic lateral sclerosis), highly active “dark microglia” which interact with blood vessels and synapses (associated with Alzheimer’s disease) and CD11c-microglia which interact with oligodendrocytes (associated with demyelination) [290]. Based on current evidence, microglia are likely to promote inflammatory and non-inflammatory responses via an involvement of NLRP3 and AIM2 inflammasomes during VCI [71, 291]. In fact, a study showed reduced proinflammatory microglia signatures in the hippocampus of mice with AIM2 deficiency upon CCH [71]. Attenuating NLRP3 inflammasome activity via pharmacological inhibitors during CCH also reduces microglial overactivation, possibly due to lower production of ROS during drug treatment [291].

Astrocytes are another immune effector cell type in the brain. Similar to microglial polarization states, activated astrocytes exist in two phenotypes based on traditional understanding: neurotoxic A1 and neuroprotective A2 astrocytes [292, 293]. Beyond this binary classification, reactive astrocytes were found to be more heterogeneous in terms of their morphology, locality, cellular interaction, and molecular expression. Therefore, the status of reactive astrocytes varies in a context-, time- and stimulus-specific manner [294]. In the context of neurodegenerative diseases, reactive astrocytes are consistently being identified with hypertrophied morphology and reduced expression of essential ion and neurotransmitter channels and receptors such as ATP-sensitive inward rectifier potassium channel 10 (Kir4.1), glial glutamate transporter 1 (GLT1), and increased expression of the glial fibrillary acidic protein (GFAP). This state of reactive astrocytes is commonly observed in A1 astrocytes that release proinflammatory and toxic mediators [294,295,296,297]. Both A1 and A2 phenotypes were present in conjunction with inflammasome activation following CCH.

Astrocytes have been shown to express NLRP1, NLRP3, AIM2 and NLRC4 receptors under different conditions. However, genetic deletion of the AIM2 receptor did not affect the expression of GFAP in either the cortex or hippocampus of mice during CCH, suggesting potential involvement of other inflammasome receptors [71, 257, 298, 299]. We recently collected unpublished data that the inflammasome signaling pathway is activated in fibrous and protoplasmic astrocytes under in vitro ischemic conditions, resulting in mature cytokine production, and apoptotic and pyroptotic cell death. Hence, we postulate that inflammasome activation may serve as a signal for astrocyte polarization.

Inflammasomes in BBB dysfunction

BBB disruption can arise from neuroinflammation, primarily through degradation of various tight junction proteins (TJPs). Matrix metalloproteinases (MMPs) released by glial cells can break down the extracellular matrix [300] and have been implicated in the disruption of the BBB under ischemic conditions [104]. MMP-2 and MMP-9 are known to be involved in BBB disruption and primarily localized to ischemic regions of astrocytic foot processes, during which TJPs undergo degradation over time [301]. Inflammasome signaling contributes to BBB dysfunction via the action of IL-1β, which can upregulate the expression and release of MMPs from glial cells [302, 303]. Application of exogenous IL-1β elicits BBB dysfunction in rat and human brain microvascular endothelium [94, 304]. In addition, both IL-1β and IL-18 can upregulate expression of various chemokines in the extracellular space and cell adhesion molecules on the endothelium [276, 305]. Cell adhesion molecules, such as ICAM-1 and VCAM, attract and facilitate immune cell infiltration into the brain during neuroinflammation. These peripheral cells can also release active MMP-9, further exacerbating BBB dysfunction [306, 307]. A recent study showed that an interleukin-1 receptor antagonist preserved BBB integrity, attenuated changes in expression and localization of TJPs and MMPs in a rat model of ischemia-reperfusion [308]. Inhibition of caspase-1 enzymatic activity in a similar model further revealed caspase-1 to induce BBB dysfunction through the activation of pyroptosis [309]. Therefore, a number of studies support a critical role of inflammasomes in BBB disruption, especially following disruption to CBF.

As an essential component of the BBB, the endothelial cell expresses a wide range of inflammasome receptors such as NLRP1, NLRP3 and NLRC4 [310]. Studies showed endothelial NLRP3 in modulating the BBB during different disease conditions, but evidence for CCH is still lacking [311,312,313]. NLRP3 may mediate BBB dysfunction for CCH based on in vitro and in vivo evidence from studies focusing on ischemic brain injury. Pharmacological inhibition of NLRP3 inflammasome activity has been shown to attenuate cerebral ischemia-induced BBB dysfunction by reducing its permeability and upregulating TJPs [313]. In addition, the study confirmed that reduced NLRP3 activity in endothelial cells increased expression of TJPs, cell viability and reduced barrier leakage [313]. This mechanism observed may explain the BBB dysfunction that is observed during CCH.

Pericytes also express the NLRP3 receptor along with other NLRP and NLRC inflammasome receptors [314]. Upon stimulation of pericytes by oxidative stress and proinflammatory mediators, in vitro cerebral pericytes demonstrated upregulation of NLRP3 and NLRC4 mRNA expression [314]. Despite an increase in inflammasome receptor mRNA expression, activation of the inflammasome complex was not detected in cerebral pericytes following exposure with a wide range of DAMPs [314]. However, as pericytes are increasingly implicated in BBB dysfunction during CCH [91, 100, 101], additional studies are needed to establish the role of inflammasomes in pericytes during VCI.

Inflammasome mediated cell death and neuronal loss

Inflammation is closely linked to cell death at the molecular level. The cell death pathway can be triggered by various proinflammatory mediators [315]. As DAMPs initiate the inflammasome signaling pathway via the NLR family and interferon-inducible protein, it activates key effector proteins such as caspase-1 and caspase-8 to cleave caspase-3, resulting in apoptosis and secondary necrosis [206, 283]. Together with the non-canonical caspase-11, these effector proteins catalyze pyroptosis via cleavage of gasdermin-D (GSDMD) [203, 208, 210]. Inhibition of caspase-1 reduces inflammasome activation and cell death in primary cortical neurons and murine microglial cells subjected to ischemia-like conditions [200, 203]. The NLRP3 inhibitor, MCC950, decreases apoptotic cell death and brain infarct size in a mouse model of ischemic stroke [316]. In a mouse model of VCI, AIM2 knockout mice expressed reduced inflammasome activity as well as apoptotic and pyroptotic cell death in neurons and microglia in the cortex and hippocampus. Similarly, a higher neuronal count was observed in the CA2 and CA3 area of the hippocampus in AIM2 knockout mice during CCH [71]. Therefore, the AIM2 inflammasome is involved in CCH-induced neuroinflammation by mediating cell death and neuronal loss during VCI disease progression.

Role of Inflammasomes in demyelination and WMLs

Numerous studies have indicated a close association of inflammasome activity with the formation of WMLs that often occur together with activated microglia [77, 203, 317]. As mentioned, activated microglia release numerous inflammatory mediators that contribute to demyelination, including IL-1β and IL-18 that are produced during inflammasome activation. IL-1β was shown to impede oligodendrocyte migration and white matter repair in mouse models of VCI [69]. Conversely, reduced secretion of IL-1β preserved myelin integrity and attenuated the formation of WMLs under CCH [71]. Anti-inflammatory pharmaceutical interventions and transgenic animal models have attenuated WML formation via suppressing microglial activation, and preventing caspase-1 and IL-1β production [70, 318, 319]. Other than in microglia, inflammasomes are also activated during CCH in oligodendrocytes. Our recent study found increased levels of cleaved caspase-1 in oligodendrocytes of mice after 30 days of BCAS [71]. Similar observations of inflammasome-mediated apoptotic and pyroptotic cell death markers were also found within oligodendrocytes. The evidence suggests that the inflammasome signaling pathway likely plays a causative role upstream of CCH-induced WML formation.

Evidence of inflammasome activity in VCI in humans

An involvement of inflammasome activation and cytokine production is related to the risk factors that drives the early disease state of VCI. In tissue samples from patients with atherosclerosis, IL-1β is detected within endothelial cells of plaque microvessels [320]. Similarly, high levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression was observed in carotid artery plaques of patients with cerebrovascular disease [321]. Studies of polymorphisms of IL-1β among small vessel disease patients, there was a higher frequency of the IL-1β allele in comparison to controls [322], suggesting that elevated levels of IL-1β may contribute to the progression of small vessel disease leading to VCI. Genetic investigation of coronary artery disease patients also found that patients carrying the G allele of NLRP3 rs10754558 had more severe coronary artery stenosis and higher levels of serum IL-1β [323]. With the G allele of NLRP3 rs10754558 enhancing the mRNA stability of NLRP3, it increases the mRNA expression of this inflammasome receptor, potentially contributing to the pathophysiology of coronary artery stenosis [323, 324]. Besides chronic vascular conditions, inflammasome activity has also been identified in VCI-associated acute conditions such as stroke [38]. By preventing binding of IL-1β with its receptor, a clinical trial showed that acute stroke patients experienced a better outcome following the administration of an interleukin-1 receptor antagonist (i.e. anakinra) [274]. This was shown by a reduction in inflammation due to lower levels of neutrophils and C-reactive proteins in the systemic circulation following a cerebral infarction. Among patients with cortical infarction, the use of an interleukin-1 receptor antagonist significantly reduced long-term disability after three months following cerebral ischemia; demonstrating the beneficial effect of reducing inflammasome activation and IL-1β secretion in cerebral vascular disease [274]. Similarly, IL-18 was shown to be more commonly associated with peripheral arterial occlusive disease, and cerebrovascular events [325], whereby an elevated level of IL-18 was shown to be evident in the plasma of acute coronary syndrome patients [326].

As the disease progresses to late-stage VCI, the actions of inflammasomes persist. In post-mortem samples from VaD patients, increases in the concentration of IL-1β was observed in the frontal cortex and hippocampus [66, 193]. Through cytokine profiling, studies of serum and plasma of VaD patients showed levels of IL-1β to be higher than in healthy controls. The relative increase in IL-1β was higher than other proinflammatory cytokines such as TNF-α and IL-6 [64, 65]. Nonetheless, some studies face challenges in detecting IL-1β in their patient samples [183, 184, 187]. For example, Mulugeta et al. did not detect any IL-1β in their patient brain tissues using ELISA kits [184]. Paganelli et al. found detectable levels of IL-1β only in 13% of all their serum samples through the same method [187]. Thus there is substantial variability in the interpretations of IL-1β in VCI because the levels present are near the limits of precise measurement by ELISA.

In addition to the presence of inflammasome-mediated proinflammatory cytokine production, immunostaining of inflammasome receptors, NLRP3 and AIM2, was greater in white matter lesions of patients with cerebral infarction [317]. Together these studies provide evidence of inflammasome activation in a severe state of VCI, highlighting the prominence of inflammasome signaling in the disease progression of VCI.

Conclusions

This review illustrates the mechanisms of inflammasome-mediated neuroinflammation under CCH in VCI. By providing direct evidence of inflammasome activation in VCI animal models and patients, we suggest that the critical involvement of the inflammasome signaling pathway in the pathogenesis of VCI may be mediated through CCH [64,65,66, 71, 118, 119, 193, 317]. Most importantly, inflammasome-mediated inflammatory mechanisms are early events that persist till the late stage of VCI; this sheds light on the inflammasome signaling pathway as a potential therapeutic target [64,65,66, 71, 118, 119, 193, 317]. By reducing inflammasome activity levels, we can attenuate its influence on various pathogenic cellular mechanisms and structural damage observed during the disease progression of VCI [119, 291]. There are clinically approved therapeutic agents that can effectively target the actions of IL-1β: anakinra, canakinumab, and rilonacept. Moreover, agents that neutralize the effects of IL-18, Tadekinig alfa and GSK1070806 are also undergoing clinical trials [327]. It is essential to keep in mind that the inflammasome signaling pathway is a significant player within our innate immune system and physiologically guards against infectious agents [328]. Hence, there is a challenge to maintain an equilibrium in reducing inflammasome activity while maintaining our defense against infectious agents. Thus, the search for therapeutic interventions that selectively target specific types of inflammasome complexes may offer a greater safety and efficacy profile in the long term, especially for chronic diseases such as VCI.

Availability of data and materials

Not applicable.

Abbreviations

ACAS:: Asymmetric Common Carotid Artery Stenosis
AD:: Alzheimer’s Disease
AIM2:: Absent in Melanoma 2
AP-1:: Activator Protein-1
ASC:: Apoptosis-associated Speck-like protein containing CARD
ATP:: Adenosine Triphosphate
BBB:: Blood-Brain Barrier
BCAS:: Bilateral Common Carotid Artery Stenosis
Bcl-2:: B-cell Lymphoma-2
C5a:: Complement Factor 5a
CAA:: Cerebral Amyloid Angiopathy
CADASIL:: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
cAMP:: Cyclic Adenosine Monophosphate
CaSRs:: Calcium-sensing receptors
CARD:: Caspase Activation and Recruitment Domain
CBF:: Cerebral Blood Flow
CCH:: Chronic Cerebral Hypoperfusion
CIITA:: MHC class II Transcription Activator
CRP:: C-reactive protein
DAMPs:: Damage-Associated Molecular Patterns
DED:: Death Effector Domains
dsDNA:: Double-stranded DNA
FIIND:: Function-to-Find Domain
GFAP:: Glial Fibrillary Acidic Protein
GLT1:: Glial Glutamate Transporter 1
GSDMD:: Gasdermin D
GSDME:: Gasdermin E
H₂O₂ :: Hydrogen Peroxide
HIF-1:: Hypoxia-Inducible Factor-1
HRP:: Horseradish Peroxidase
ICAM:: Intercellular Adhesion Molecule
IFN:: Type I interferon
IL-1β:: Interleukin-1β
IL-6:: Interleukin-6
Kir4.1:: ATP-sensitive Inward Rectifier Potassium Channel 10
LPC:: Lysophosphatidylcholine
LPS:: Lipopolysaccharides
LRR:: Leucine-Rich Repeat
MALT1:: Mucosa-Associated Lymphoid tissue lymphoma Translocation protein-1
MAPKs:: Mitogen-Activated Protein Kinases
MID:: Multi-Infarct Dementia
MMPs:: Matrix Metalloproteinases
MPB:: Myelin Basic Protein
mtROS:: Mitochondrial ROS
NADPH:: Nicotinamide Adenine Dinucleotide Phosphate
NAIP:: NLR Apoptosis Inhibitory Protein
NAIP:: NLR Apoptosis Inhibitory Protein
NF-κB:: Nuclear Factor Kappa B
NLR:: Nod-Like Receptor
NLR:: Nucleotide-binding ligomerization domain-like receptor
NLRC4:: NLR-CARD Containing 4
NT-GSDMD:: N-terminal fragment GSDMD
NT-GSDME:: N-terminal fragment GSDME
OH^- :: Hydroxyl Radical
oxPAPC:: Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine
P2X4:: P2X purinoceptor 4
P2X7:: P2X purinoceptor 7
PAMPs:: Pathogen-Associated Molecular Patterns
PLA₂ :: Phospholipase A2
PKR:: Protein kinase R
PRRs:: Pattern Recognition Receptors
PYD:: Pyrin
PYHIN:: Nuclear localization (HIN) domain-containing
RAGE:: Receptor for Advanced Glycation End-products
RIPK1:: Receptor-Interacting serine/threonine Kinase 1
ROS:: Reactive Oxygen Species
SVD:: Small Vessel Disease
TJPs:: Tight Junction Proteins
TLRs:: Toll-Like Receptors
TNF:: Tumor Necrosis Factor
TP1:: Telomerase-associated Protein
TRPM2:: Transient receptor potential melastatin 2
TXNIP:: Thioredoxin-interacting protein
TRX:: Thioredoxin
UCCAO:: Unilateral Common Carotid Artery Occlusion
VaD:: Vascular Dementia
VCAM:: Vascular Cell Adhesion Molecule
VCI:: Vascular Cognitive Impairment
WML:: White Matter Lesion

References

World Health Organization, Alzheimer’s disease international. Dementia: a public health priority. 2012 [cited 2021 Jan 24]. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia.
Google Scholar
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75.e2 [cited 2018 Sep 13] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23305823.
Article PubMed Google Scholar
Lobo A, Launer LJ, Fratiglioni L, Andersen K, Di Carlo A, Breteler MMB, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurology. 2000;54(11 SUPPL. 5):S4–9.
CAS PubMed Google Scholar
Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, et al. Incidence of dementia, Alzheimer’s disease, and vascular dementia in Italy. The ILSA study. J Am Geriatr Soc. 2002;50(1):41–8 [cited 2020 Aug 26] Available from: https://pubmed.ncbi.nlm.nih.gov/12028245/.
Article PubMed Google Scholar
Fujihara S, Brucki SMD, Rocha MSG, Carvalho AA, Piccolo AC. Prevalence of presenile dementia in a tertiary outpatient clinic. Arq Neuropsiquiatr. 2004;62(3 A):592–5 [cited 2020 Aug 26] Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-282X2004000400005&lng=en&nrm=iso&tlng=en.
Article PubMed Google Scholar
Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, et al. Alzheimer’s disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008;7:812–26 Lancet Publishing Group [cited 2020 Aug 26] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860610/.
Article PubMed PubMed Central Google Scholar
Chan KY, Wu JJ, Liu L, Theodoratou E, Car J, Middleton L, et al. Epidemiology of alzheimer’s disease and other forms of dementia in China, 1990-2010: a systematic review and analysis. Lancet. 2013;381(9882):2016–23 [cited 2020 Aug 26] Available from: https://pubmed.ncbi.nlm.nih.gov/23746902/.
Article PubMed Google Scholar
Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:2672–713.
Article PubMed PubMed Central Google Scholar
Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction—the disregarded partner of Alzheimer’s disease. Alzheimers Dement. 2019;15:158–67 [cited 2021 Jan 24] Available from: https://pubmed.ncbi.nlm.nih.gov/30642436/.
Article PubMed PubMed Central Google Scholar
Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69(24):2197–204 [cited 2020 Aug 26] Available from: https://pubmed.ncbi.nlm.nih.gov/17568013/.
Article PubMed Google Scholar
Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s coordinating Centre. Brain. 2013;136(9):2697–706 [cited 2020 Aug 26] Available from: https://pubmed.ncbi.nlm.nih.gov/23842566/.
Article PubMed PubMed Central Google Scholar
O’Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular cognitive impairment. Lancet Neurol. 2003;2(2):89–98.
Article PubMed Google Scholar
Van Der Flier WM, Skoog I, Schneider JA, Pantoni L, Mok V, Chen CLH, et al. Vascular cognitive impairment. Nat Rev Dis Prim. 2018;4:18003.
Article PubMed Google Scholar
Román GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol. 2002;1(7):426–36 [cited 2018 Oct 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12849365.
Article PubMed Google Scholar
Sachdev P, Kalaria R, O’Brien J, Skoog I, Alladi S, Black SE, et al. Diagnostic Criteria for Vascular Cognitive Disorders. Alzheimer Dis Assoc Disord. 2014;28(3):206–18.
Article CAS PubMed PubMed Central Google Scholar
Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701 [cited 2020 Aug 22] Available from: https://pubmed.ncbi.nlm.nih.gov/20610345/.
Article PubMed Google Scholar
Cosentino F, Battista R, Scuteri A, De Sensi F, De Siati L, Di Russo C, et al. Impact of fasting glycemia and regional cerebral perfusion in diabetic subjects: a study with technetium-99m-ethyl cysteinate dimer single photon emission computed tomography. Stroke. 2009;40(1):306–8 [cited 2020 Dec 13] Available from: https://www.ahajournals.org/doi/10.1161/STROKEAHA.108.520627.
Article CAS PubMed Google Scholar
Chen JJ, Rosas HD, Salat DH. Age-associated reductions in cerebral blood flow are independent from regional atrophy. Neuroimage. 2011;55(2):468–78 [cited 2020 Dec 13] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435846/.
Article PubMed Google Scholar
Muller M, van der Graaf Y, Visseren FL, WPTM M, Geerlings MI. Hypertension and longitudinal changes in cerebral blood flow: the SMART-MR study. Ann Neurol. 2012;71(6):825–33 [cited 2020 Dec 13] Available from: http://doi.wiley.com/10.1002/ana.23554.
Article PubMed Google Scholar
Román GC. Brain hypoperfusion: a critical factor in vascular dementia. Neurol Res. 2004;26(5):454–8 [cited 2018 Sep 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15265263.
Article PubMed Google Scholar
Hilal S, Xu X, Ikram MK, Vrooman H, Venketasubramanian N, Chen C. Intracranial stenosis in cognitive impairment and dementia. J Cereb Blood Flow Metab. 2017;37(6):2262–9 [cited 2021 Jan 19] Available from: http://journals.sagepub.com/doi/10.1177/0271678X16663752.
Article PubMed Google Scholar
Ferro DA, Mutsaerts HJJM, Hilal S, Kuijf HJ, Petersen ET, Petr J, et al. Cortical microinfarcts in memory clinic patients are associated with reduced cerebral perfusion. J Cereb Blood Flow Metab. 2020;40(9):1869–78 [cited 2021 Jan 19] Available from: https://pubmed.ncbi.nlm.nih.gov/31558107/.
Article CAS PubMed Google Scholar
Schuff N, Matsumoto S, Kmiecik J, Studholme C, Du A, Ezekiel F, et al. Cerebral blood flow in ischemic vascular dementia and Alzheimer’s disease, measured by arterial spin-labeling magnetic resonance imaging. Alzheimers Dement. 2009;5(6):454–62 [cited 2018 Sep 27] Available from: http://www.ncbi.nlm.nih.gov/pubmed/19896584.
Article PubMed PubMed Central Google Scholar
Ciacciarelli A, Sette G, Giubilei F, Orzi F. Chronic cerebral hypoperfusion: an undefined, relevant entity. J Clin Neurosci Churchill Livingstone. 2020;73:8–12 [cited 2021 Mar 11] Available from: https://pubmed.ncbi.nlm.nih.gov/31948882/.
Article Google Scholar
Duncombe J, Kitamura A, Hase Y, Ihara M, Kalaria RN, Horsburgh K. Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin Sci. 2017;131(19):2451–68 [cited 2020 Jun 7] Available from: https://portlandpress.com/clinsci/article/131/19/2451/71528/Chronic-cerebral-hypoperfusion-a-key-mechanism.
Article CAS Google Scholar
Wolters FJ, Zonneveld HI, Hofman A, van der Lugt A, Koudstaal PJ, Vernooij MW, et al. Cerebral perfusion and the risk of dementia. Circulation. 2017;136(8):719–28 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/28588075.
Article PubMed Google Scholar
Kawamura J, Meyer JS, Terayama Y, Weathers S. Leukoaraiosis correlates with cerebral hypoperfusion in vascular dementia. Stroke. 1991;22(5):609–14 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2028490.
Article CAS PubMed Google Scholar
APA A, Van Der Graaf Y, Vincken KL, WPTM M, Geerlings MI. Combined effect of cerebral hypoperfusion and white matter lesions on executive functioning - the SMART-MR study. Dement Geriatr Cogn Disord. 2010;29(3):240–7 [cited 2020 Dec 13] Available from: https://pubmed.ncbi.nlm.nih.gov/20375504/.
Article Google Scholar
Moskowitz MA, Lo EH, Iadecola C. The science of stroke: Mechanisms in search of treatments. Neuron. NIH Public Access. 2010;67:181–98 [cited 2020 Dec 13] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957363/.
CAS Google Scholar
Wallin A, Blennow K, Fredman P, Gottfries CG, Karlsson I, Svenner-holm L. Blood brain barrier function in vascular dementia. Acta Neurol Scand. 2009;81(4):318–22 [cited 2019 Aug 22] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2360399.
Article Google Scholar
Bouhrara M, Reiter DA, Bergeron CM, Zukley LM, Ferrucci L, Resnick SM, et al. Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content. Alzheimer’s Dement. 2018;14(8):998–1004 [cited 2020 Dec 13] Available from: https://pubmed.ncbi.nlm.nih.gov/29679574/.
Article Google Scholar
Low A, Mak E, Malpetti M, Passamonti L, Nicastro N, Stefaniak JD, et al. In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2021;92(1):45–52. [cited 2020 Dec 13] Available from:. https://doi.org/10.1136/jnnp-2020-323894.
Article Google Scholar
Venkat P, Chopp M, Chen J. Models and mechanisms of vascular dementia. Exp Neurol. 2015;272:97–108 [cited 2018 Oct 8] Available from: http://www.ncbi.nlm.nih.gov/pubmed/25987538.
Article PubMed PubMed Central Google Scholar
Washida K, Hattori Y, Ihara M. Animal models of chronic cerebral hypoperfusion: From mouse to primate. Int J Mol Sci. MDPI AG. 2019;20:6176 [cited 2020 Dec 13]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941004/.
Article CAS Google Scholar
Li W, Liu H, Jiang H, Wang C, Guo Y, Sun Y, et al. (S)-Oxiracetam is the Active Ingredient in Oxiracetam that Alleviates the Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats. Sci Rep. 2017;7(1):10052 [cited 2021 Nov 2] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577264/.
Article PubMed PubMed Central Google Scholar
Hertz L. Bioenergetics of cerebral ischemia: A cellular perspective. Neuropharmacology. 2008;55(3):289–309 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/18639906/.
Article CAS PubMed Google Scholar
Matute C, Alberdi E, Ibarretxe G, Sánchez-Gómez MV. Excitotoxicity in glial cells. Eur J Pharmacol. 2002;447(2–3):239–46.
Article CAS PubMed Google Scholar
Fann DY-W, Lee S-Y, Manzanero S, Chunduri P, Sobey CG, Arumugam TV. Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev. 2013;12(4):941–66 [cited 2016 Jan 22] Available from: http://www.ncbi.nlm.nih.gov/pubmed/24103368.
Article CAS PubMed Google Scholar
Du J, Ma M, Zhao Q, Fang L, Chang J, Wang Y, et al. Mitochondrial bioenergetic deficits in the hippocampi of rats with chronic ischemia-induced vascular dementia. Neuroscience. 2013;231:345–52 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/23232258/.
Article CAS PubMed Google Scholar
Plaschke K, Weigand MA, Michel A, Martin E, Bardenheuer HJ. Permanent cerebral hypoperfusion: ‘Preconditioning-like’ effects on rat energy metabolism towards acute systemic hypotension. Brain Res. 2000;858(2):363–70 [cited 2021 Oct 31] Available from: https://pubmed.ncbi.nlm.nih.gov/10708688/.
Article CAS PubMed Google Scholar
Aliev G, Smith MA, Obrenovich ME, De La Torre JC, Perry G. Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease. Neurotox Res. 2003;5:491–504 [cited 2021 Nov 15] Available from: https://pubmed.ncbi.nlm.nih.gov/14715433/.
Article PubMed Google Scholar
Liu L, Li CJ, Lu Y, Zong XG, Luo C, Sun J, et al. Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion. Sci Rep. 2015;5(1):14474 [cited 2021 Mar 12] Available from: www.nature.com/scientificreports.
Article CAS PubMed PubMed Central Google Scholar
Sheng N, Zheng H, Li M, Li M, Wang Z, Peng Y, et al. 4,5 caffeoylquinic acid and scutellarin, identified by integrated metabolomics and proteomics approach as the active ingredients of Dengzhan Shengmai, act against chronic cerebral hypoperfusion by regulating glutamatergic and GABAergic synapses. Pharmacol Res. 2020;152:104636 [cited 2021 Nov 2] Available from: https://pubmed.ncbi.nlm.nih.gov/31926275/.
Article CAS PubMed Google Scholar
Huang J, Li J, Feng C, Huang X, Wong L, Liu X, et al. Blood-Brain Barrier Damage as the Starting Point of Leukoaraiosis Caused by Cerebral Chronic Hypoperfusion and Its Involved Mechanisms: Effect of Agrin and Aquaporin-4. Biomed Res Int. 2018;2018:2321797 [cited 2021 3] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846350/.
Article PubMed PubMed Central Google Scholar
Jayant S, Sharma B. Selective Modulator of Cannabinoid Receptor Type 2 Reduces Memory Impairment and Infarct Size During Cerebral Hypoperfusion and Vascular Dementia. Curr Neurovasc Res. 2016;13(4):289–302 [cited 2021 Nov 3] Available from: https://pubmed.ncbi.nlm.nih.gov/27586843/.
Article CAS PubMed Google Scholar
Mongin AA. Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm. Pathophysiology. 2007;14(3–4):183–93 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/17961999/.
Article CAS PubMed PubMed Central Google Scholar
Yanpallewar SU, Hota D, Rai S, Kumar M, Acharya SB. Nimodipine attenuates biochemical, behavioral and histopathological alterations induced by acute transient and long-term bilateral common carotid occlusion in rats. Pharmacol Res. 2004;49(2):143–50 [cited 2021 Nov 3] Available from: https://pubmed.ncbi.nlm.nih.gov/14643694/.
Article CAS PubMed Google Scholar
Nimmrich V, Eckert A. Calcium channel blockers and dementia. Br J Pharmacol. 2013;169:1203–10 [cited 2021 Nov 3] Available from: https://pubmed.ncbi.nlm.nih.gov/23638877/.
Article CAS PubMed PubMed Central Google Scholar
Orgogozo J-M, Rigaud A-S, Stöffler A, Möbius H-J, Forette F. Efficacy and safety of Memantine in patients with mild to moderate vascular dementia. Stroke. 2002;33(7):1834–9.
Article CAS PubMed Google Scholar
Ganzella M, De Oliveira EDA, Comassetto DD, Cechetti F, Cereser VH, Moreira JD, et al. Effects of chronic guanosine treatment on hippocampal damage and cognitive impairment of rats submitted to chronic cerebral hypoperfusion. Neurol Sci. 2012;33(5):985–97 [cited 2021 Nov 15] Available from: https://pubmed.ncbi.nlm.nih.gov/22167652/.
Article PubMed Google Scholar
Solenski NJ, DiPierro CG, Trimmer PA, Kwan AL, Helms GA. Ultrastructural changes of neuronal mitochondria after transient and permanent cerebral ischemia. Stroke. 2002;33(3):816–24 [cited 2021 Feb 19] Available from: https://www.ahajournals.org/doi/10.1161/hs0302.104541.
Article PubMed Google Scholar
De La Torre JC, Aliev G. Inhibition of vascular nitric oxide after rat chronic brain hypoperfusion: Spatial memory and immunocytochemical changes. J Cereb Blood Flow Metab. 2005;25(6):663–72 [cited 2021 Feb 19] Available from: https://pubmed.ncbi.nlm.nih.gov/15703700/.
Article PubMed Google Scholar
Abramov AY, Scorziello A, Duchen MR. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J Neurosci. 2007;27(5):1129–38 [cited 2021 Feb 19] Available from: https://pubmed.ncbi.nlm.nih.gov/17267568/.
Article CAS PubMed PubMed Central Google Scholar
Ono T, Tsuruta R, Fujita M, Aki HS, Kutsuna S, Kawamura Y, et al. Xanthine oxidase is one of the major sources of superoxide anion radicals in blood after reperfusion in rats with forebrain ischemia/reperfusion. Brain Res. 2009;1305:158–67 [cited 2021 Feb 19] Available from: https://pubmed.ncbi.nlm.nih.gov/19781528/.
Article CAS PubMed Google Scholar
Choi DH, Lee KH, Kim JH, Seo JH, Kim HY, Shin CY, et al. NADPH oxidase 1, a novel molecular source of ROS in hippocampal neuronal death in vascular dementia. Antioxidants Redox Signal. 2014;21(4):533–50 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/24294978/.
Article CAS Google Scholar
McCord JM, Roy RS. The pathophysiology of superoxide: Roles in inflammation and ischemia. Can J Physiol Pharmacol. 1982;60(11):1346–52 [cited 2021 Feb 19] Available from: https://pubmed.ncbi.nlm.nih.gov/6295573/.
Article CAS PubMed Google Scholar
Radi R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. Proc Natl Acad Sci U S A. 2018;115(23):5839–48 [cited 2021 Feb 19] Available from: www.pnas.org/cgi/doi/10.1073/pnas.1804932115.
Article CAS PubMed PubMed Central Google Scholar
Yamagishi S, Nakamura K, Matsui T. Role of Oxidative Stress in the Development of Vascular Injury and its Therapeutic Intervention by Nifedipine. Curr Med Chem. 2008;15(2):172–7 [cited 2020 Dec 29] Available from: https://pubmed.ncbi.nlm.nih.gov/18220772/.
Article CAS PubMed Google Scholar
Gustaw-Rothenberg K, Kowalczuk K, Stryjecka-Zimmer M. Lipids’ peroxidation markers in Alzheimer’s disease and vascular dementia. Geriatr Gerontol Int. 2010;10(2):161–6 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/20446930/.
PubMed Google Scholar
Gackowski D, Rozalski R, Siomek A, Dziaman T, Nicpon K, Klimarczyk M, et al. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J Neurol Sci. 2008;266(1–2):57–62 [cited 2021 May 17] Available from: https://pubmed.ncbi.nlm.nih.gov/17888453/.
Article CAS PubMed Google Scholar
Ryglewicz D, Rodo M, Kunicki PK, Bednarska-Makaruk M, Graban A, Lojkowska W, et al. Plasma antioxidant activity and vascular dementia. J Neurol Sci. 2002;203(204):195–7 [cited 2021 Sep 15] Available from: https://pubmed.ncbi.nlm.nih.gov/12417383/.
Article PubMed Google Scholar
Chen GY, Nuñez G. Sterile inflammation: Sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37 [cited 2020 Dec 27] Available from: https://pubmed.ncbi.nlm.nih.gov/21088683/.
Article CAS PubMed PubMed Central Google Scholar
Newton K, Dixit VM. Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol. 2012;4(3) [cited 2020 Dec 27] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3282411/.
Zuliani G, Ranzini M, Guerra G, Rossi L, Munari MR, Zurlo A, et al. Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res. 2007;41(8):686–93 [cited 2018 Oct 12] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16600299.
Article CAS PubMed Google Scholar
Schmitz M, Hermann P, Oikonomou P, Stoeck K, Ebert E, Poliakova T, et al. Cytokine profiles and the role of cellular prion protein in patients with vascular dementia and vascular encephalopathy. Neurobiol Aging. 2015;36(9):2597–606 [cited 2018 Oct 12] Available from: http://www.ncbi.nlm.nih.gov/pubmed/26170132.
Article CAS PubMed Google Scholar
Belkhelfa M, Beder N, Mouhoub D, Amri M, Hayet R, Tighilt N, et al. The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia. J Neuroimmunol. 2018;320:48–57 [cited 2018 Oct 12] Available from: http://www.ncbi.nlm.nih.gov/pubmed/29759140.
Article CAS PubMed Google Scholar
Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, et al. Inflammatory Proteins in Plasma and the Risk of Dementia. Arch Neurol. 2004;61(5):668 [cited 2018 Oct 12] Available from: http://archneur.jamanetwork.com/article.aspx?doi=10.1001/archneur.61.5.668.
Article PubMed Google Scholar
Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78(2):151–6 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15378607.
Article CAS PubMed Google Scholar
Zhou Y, Zhang J, Wang L, Chen Y, Wan Y, He Y, et al. Interleukin-1β impedes oligodendrocyte progenitor cell recruitment and white matter repair following chronic cerebral hypoperfusion. Brain Behav Immun. 2017;60:93–105 [cited 2018 Oct 13] Available from: http://www.ncbi.nlm.nih.gov/pubmed/27663285.
Article CAS PubMed Google Scholar
Miyanohara J, Kakae M, Nagayasu K, Nakagawa T, Mori Y, Arai K, et al. TRPM2 channel aggravates CNS inflammation and cognitive impairment via activation of Microglia in Chronic cerebral Hypoperfusion. J Neurosci. 2018;38(14):3520–33.
Article CAS PubMed PubMed Central Google Scholar
Poh L, Fann DY, Wong P, Lim HM, Foo SL, Kang S-W, et al. AIM2 inflammasome mediates hallmark neuropathological alterations and cognitive impairment in a mouse model of vascular dementia. Mol Psychiatry. 2020; [cited 2020 Dec 27]; Available from: http://www.nature.com/articles/s41380-020-00971-5.
Liu Q, He S, Groysman L, Shaked D, Russin J, Cen S, et al. White matter injury due to experimental chronic cerebral hypoperfusion is associated with C5 deposition. Stover CM, editor. PLoS One. 2013;8(12):e84802 [cited 2020 Jun 7] Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094516.
Article PubMed PubMed Central Google Scholar
Gülke E, Gelderblom M, Magnus T. Danger signals in stroke and their role on microglia activation after ischemia. Ther Adv Neurol Dis. SAGE Publications Ltd. 2018;11:1756286418774254 [cited 2021 Feb 19]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968660/.
Google Scholar
Pascual O, Ben AS, Rostaing P, Triller A, Bessis A. Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A. 2012;109(4):E197–205 [cited 2018 Oct 12] Available from: www.pnas.org/cgi/doi/10.1073/pnas.1111098109.
Article CAS PubMed Google Scholar
Tomimoto H, Akiguchi I, Suenaga T, Nishimura M, Wakita H, Nakamura S, et al. Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer’s disease patients. Stroke. 1996;27(11):2069–74 [cited 2018 Oct 12] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8898818.
Article CAS PubMed Google Scholar
Fernando MS, Simpson JE, Matthews F, Brayne C, Lewis CE, Barber R, et al. White matter lesions in an unselected cohort of the elderly: Molecular pathology suggests origin from chronic hypoperfusion injury. Stroke. 2006;37(6):1391–8 [cited 2018 Oct 12] Available from: https://www.ahajournals.org/doi/10.1161/01.STR.0000221308.94473.14.
Article PubMed Google Scholar
Simpson JE, Fernando MS, Clark L, Ince PG, Matthews F, Forster G, et al. White matter lesions in an unselected cohort of the elderly: Astrocytic, microglial and oligodendrocyte precursor cell responses. Neuropathol Appl Neurobiol. 2007;33(4):410–9 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/17442062.
Article CAS PubMed Google Scholar
Häußler V, Daehn T, Rissiek B, Roth V, Gerloff C, Arumugam TV, et al. Intravenous Immunoglobulin (IVIg) Induce a Protective Phenotype in Microglia Preventing Neuronal Cell Death in Ischaemic Stroke. NeuroMolecular Med. 2020;22(1):121–32 [cited 2021 May 17] Available from: https://pubmed.ncbi.nlm.nih.gov/31559534/.
Article PubMed Google Scholar
Marín-Teva JL, Cuadros MA, Martín-Oliva D, Navascués J. Microglia and neuronal cell death. Neuron Glia Biol. 2011;7(1):25–40 [cited 2019 Jul 18] Available from: https://www.cambridge.org/core/product/identifier/S1740925X12000014/type/journal_article.
Article PubMed Google Scholar
Grammas P. Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer’s disease. J Neuroinflammation. BioMed Central. 2011;8:26 [cited 2020 Dec 27] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072921/.
Article CAS Google Scholar
Zegeye MM, Andersson B, Sirsjö A, Ljungberg LU. IL-6 trans-Signaling Impairs Sprouting Angiogenesis by Inhibiting Migration, Proliferation and Tube Formation of Human Endothelial Cells. Cells. 2020;9(6):1414 [cited 2020 Dec 27] Available from: https://pubmed.ncbi.nlm.nih.gov/32517159/.
Article CAS PubMed Central Google Scholar
Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV. Effects of the Chemokine CCL2 on Blood–Brain Barrier Permeability during Ischemia–Reperfusion Injury. J Cereb Blood Flow Metab. 2006;26(6):797–810 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16192992.
Article CAS PubMed Google Scholar
Sumi N, Nishioku T, Takata F, Matsumoto J, Watanabe T, Shuto H, et al. Lipopolysaccharide-activated microglia induce dysfunction of the blood-brain barrier in rat microvascular endothelial cells co-cultured with microglia. Cell Mol Neurobiol. 2010;30(2):247–53 [cited 2020 Dec 27] Available from: https://pubmed.ncbi.nlm.nih.gov/19728078/.
Article CAS PubMed Google Scholar
Preston M, Gong X, Su W, Matsumoto SG, Banine F, Winkler C, et al. Digestion products of the PH20 hyaluronidase inhibit remyelination. Ann Neurol. 2013;73(2):266–80 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/23463525.
Article CAS PubMed PubMed Central Google Scholar
Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev. 2004;84(3):869–901.
Article CAS PubMed Google Scholar
Hill J, Rom S, Ramirez SH, Persidsky Y. Emerging Roles of Pericytes in the Regulation of the Neurovascular Unit in Health and Disease. J Neuroimmune Pharmacol. NIH Public Access. 2014;9:591–605 [cited 2021 Sep 15] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209199/.
Article Google Scholar
Chai Q, He WQ, Zhou M, Lu H, Fu ZF. Enhancement of Blood-Brain Barrier Permeability and Reduction of Tight Junction Protein Expression Are Modulated by Chemokines/Cytokines Induced by Rabies Virus Infection. J Virol. 2014;88(9):4698–710 [cited 2021 Mar 13] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993813/.
Article PubMed PubMed Central Google Scholar
Komarova YA, Kruse K, Mehta D, Malik AB. Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability. Circ Res. Lippincott Williams and Wilkins. 2017;120:179–206 [cited 2021 Mar 13] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225667/.
CAS Google Scholar
Rao R. Oxidative stress-induced disruption of epithelial and endothelial tight junctions. Front Biosci. 2008;13(18):7210–26 [cited 2021 Feb 19] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261932/.
Article CAS PubMed PubMed Central Google Scholar
De Vries HE, Blom-Roosemalen MCM, Van Oosten M, De Boer AG, Van Berkel TJC, Breimer DD, et al. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol. 1996;64(1):37–43 [cited 2021 Feb 19] Available from: https://pubmed.ncbi.nlm.nih.gov/8598388/.
Article PubMed Google Scholar
Liu Q, Radwanski R, Babadjouni R, Patel A, Hodis DM, Baumbacher P, et al. Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood–brain barrier permeability in the corpus callosum. J Cereb Blood Flow Metab. 2019;39(2):240–50 [cited 2021 Jan 8] Available from: https://pubmed.ncbi.nlm.nih.gov/29192539/.
Article PubMed Google Scholar
Lopez-Ramirez MA, Fischer R, Torres-Badillo CC, Davies HA, Logan K, Pfizenmaier K, et al. Role of Caspases in Cytokine-Induced Barrier Breakdown in Human Brain Endothelial Cells. J Immunol. 2012;189(6):3130–9 [cited 2021 Feb 19] Available from: https://pubmed.ncbi.nlm.nih.gov/22896632/.
Article CAS PubMed Google Scholar
Takeshita Y, Ransohoff RM. Inflammatory cell trafficking across the blood-brain barrier: chemokine regulation and in vitro models. Immunol Rev. 2012;248(1):228–39 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22725965.
Article PubMed PubMed Central Google Scholar
Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. Interleukin-1β-induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: A magnetic resonance study. J Neurosci. 2000;20(21):8153–9 [cited 2021 Jan 8] Available from: https://www.jneurosci.org/content/20/21/8153.
Article CAS PubMed PubMed Central Google Scholar
Ihara M, Tomimoto H, Kinoshita M, Oh J, Noda M, Wakita H, et al. Chronic cerebral Hypoperfusion induces MMP-2 but not MMP-9 expression in the Microglia and vascular endothelium of White matter. J Cereb Blood Flow Metab. 2001;21(7):828–34.
Article CAS PubMed Google Scholar
Wardlaw JM, Sandercock PAG, Dennis MS, Starr J. Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke. 2003;34(3):806–12.
Article CAS PubMed Google Scholar
Wardlaw JM, Doubal F, Armitage P, Chappell F, Carpenter T, Muñoz Maniega S, et al. Lacunar stroke is associated with diffuse Blood-Brain barrier dysfunction. Ann Neurol. 2009;65(2):194–202.
Article PubMed Google Scholar
Ueno M, Tomimoto H, Akiguchi I, Wakita H, Sakamoto H. Blood–Brain barrier disruption in White matter Lesions in a rat model of Chronic cerebral Hypoperfusion. J Cereb Blood Flow Metab. 2002;22(1):97–104.
Article PubMed Google Scholar
Huang J, Li J, Feng C, Huang X, Wong L, Liu X, et al. Blood-Brain Barrier Damage as the Starting Point of Leukoaraiosis Caused by Cerebral Chronic Hypoperfusion and Its Involved Mechanisms: Effect of Agrin and Aquaporin-4. Biomed Res Int. 2018;2018:1–10 [cited 2020 Jun 10] Available from: https://www.hindawi.com/journals/bmri/2018/2321797/.
Google Scholar
Lee JM, Lee JH, Song MK, Kim YJ. Nxp031 improves cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia rat model through nrf2 signaling. Int J Mol Sci. 2021;22(12):6285 [cited 2021 Sep 15] Available from: https://www.mdpi.com/1422-0067/22/12/6285/htm.
Article CAS PubMed PubMed Central Google Scholar
Sun Z, Gao C, Gao D, Sun R, Li W, Wang F, et al. Reduction in pericyte coverage leads to blood–brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion. Fluids Barriers CNS. 2021;18(1):1–18 [cited 2021 Sep 15] Available from: https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-021-00255-2.
Article Google Scholar
Wallin A, Sjögren M, Edman Å, Blennow K, Regland B. Symptoms, vascular risk factors and Blood-Brain barrier function in relation to CT White-matter changes in dementia. Eur Neurol. 2000;44(4):229–35.
Article CAS PubMed Google Scholar
Janyou A, Wicha P, Jittiwat J, Suksamrarn A, Tocharus C, Tocharus J. Dihydrocapsaicin Attenuates Blood Brain Barrier and Cerebral Damage in Focal Cerebral Ischemia/Reperfusion via Oxidative Stress and Inflammatory. Sci Rep. 2017;7(1):10556 [cited 2020 Dec 27] Available from: https://pubmed.ncbi.nlm.nih.gov/28874782/.
Article PubMed PubMed Central Google Scholar
Varatharaj A, Galea I. The blood-brain barrier in systemic inflammation. Brain Behav Immunity Feb. 2017;1:1–12 Availaeble from: https://www.sciencedirect.com/science/article/pii/S0889159116300551.
Google Scholar
Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron. 1995;15(4):961–73.
Article CAS PubMed Google Scholar
Yamashima T. Ca2+−dependent proteases in ischemic neuronal death. A conserved ‘calpain-cathepsin cascade’ from nematodes to primates. Cell Calcium. 2004;36(3–4):285–93 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/15261484/.
Article CAS PubMed Google Scholar
Lee BI, Lee DJ, Cho KJ, Kim GW. Early nuclear translocation of endonuclease G and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Neurosci Lett. 2005;386(1):23–7 [cited 2020 Dec 24] Available from: https://pubmed.ncbi.nlm.nih.gov/15979239/.
Article CAS PubMed Google Scholar
Xu Y, Bradham C, Brenner DA, Czaja MJ. Hydrogen peroxide-induced liver cell necrosis is dependent on AP-1 activation. Am J Physiol Liver Physiol. 1997;273(4):G795–803 [cited 2021 Feb 19] Available from: https://www.physiology.org/doi/10.1152/ajpgi.1997.273.4.G795.
CAS Google Scholar
Lee JE, Sohn J, Lee JH, Lee KC, Son CS, Tockgo YC. Regulation of bcl-2 family in hydrogen peroxide-induced apoptosis in human leukemia HL-60 cells. Exp Mol Med. 2000;32(1):42–6 [cited 2021 Feb 19] Available from: https://www.nature.com/articles/emm20008.
Article CAS PubMed Google Scholar
Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114(2):181–90 [cited 2021 Jan 5] Available from: https://pubmed.ncbi.nlm.nih.gov/12887920/.
Article CAS PubMed Google Scholar
Fisher CM. Lacunar strokes and infarcts: A review. Neurology. 1982;32(8):871–6 [cited 2020 Sep 26] Available from: https://pubmed.ncbi.nlm.nih.gov/7048128/.
Article CAS PubMed Google Scholar
Rami A, Kögel D. Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin? Autophagy. Taylor and Francis Inc. 2008;4:422–6 [cited 2020 Dec 29] Available from: https://pubmed.ncbi.nlm.nih.gov/18319639/.
CAS Google Scholar
Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57 [cited 2020 Dec 29] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2008650/.
Article CAS PubMed PubMed Central Google Scholar
Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol Rev. 2003;193:10–21 [cited 2020 Dec 29] Available from: https://pubmed.ncbi.nlm.nih.gov/12752666/.
Article CAS PubMed Google Scholar
Gray F, Polivka M, Viswanathan A, Baudrimont M, Bousser M-G, Chabriat H. Apoptosis in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. 2007;66(7):597–607 [cited 2020 Jun 8] Available from: https://academic.oup.com/jnen/article-lookup/doi/10.1097/nen.0b013e318093e574.
Article PubMed Google Scholar
Sun ZK, Ma XR, Jia YJ, Liu YR, Zhang JW, Zhang BA. Effects of resveratrol on apoptosis in a rat model of vascular dementia. Exp Ther Med. 2014;7(4):843–8.
Article CAS PubMed PubMed Central Google Scholar
Guo L, Wang D, Xu Y, Cui K. Effects of IL-1β on Hippocampus Cell Apoptosis and Learning Ability of Vascular Dementia Rats. Eur Rev Med Pharmacol Sci. 2018;22(18):6042–8 [cited 2020 Jun 8] Available from: https://pubmed.ncbi.nlm.nih.gov/30280789/.
PubMed Google Scholar
Poh L, Razak SMBA, Lim HM, Lai MKP, Chen CL-H, Lim LHK, et al. AIM2 inflammasome mediates apoptotic and pyroptotic death in the cerebellum following chronic hypoperfusion. Exp Neurol. 2021;346:113856 [cited 2021 Sep 8] Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014488621002648.
Article CAS PubMed Google Scholar
Poh L, Rajeev V, Selvaraji S, Lai MKP, Chen CLH, Arumugam TV, et al. Intermittent fasting attenuates inflammasome-associated apoptotic and pyroptotic death in the brain following chronic hypoperfusion. Neurochem Int. 2021;148:105109 [cited 2021 Jul 28] Available from: https://pubmed.ncbi.nlm.nih.gov/34174333/.
Article CAS PubMed Google Scholar
Kövari E, Gold G, Herrmann FR, Canuto A, Hof PR, Michel JP, et al. Cortical Microinfarcts and Demyelination Significantly Affect Cognition in Brain Aging. Stroke. 2004;35(2):410–4 [cited 2021 Jan 2] Available from: https://www.ahajournals.org/doi/10.1161/01.STR.0000110791.51378.4E.
Article PubMed Google Scholar
Rosenberg GA. Inflammation and white matter damage in vascular cognitive impairment. In: Stroke. Stroke. 2009;40:S20–3 [cited 2021 Jan 2] Available from: https://pubmed.ncbi.nlm.nih.gov/19064797/.
Article PubMed Google Scholar
Love S. Demyelinating diseases. J Clin Pathol. BMJ Publishing Group. 2006;59:1151–9 [cited 2021 Jan 2] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860500/.
CAS Google Scholar
Krick S, Eul BG, Hänze J, Savai R, Grimminger F, Seeger W, et al. Role of hypoxia-inducible factor-1α in hypoxia-induced apoptosis of primary alveolar epithelial type II cells. Am J Respir Cell Mol Biol. 2005;32(5):395–403 [cited 2021 Jan 2] Available from: https://pubmed.ncbi.nlm.nih.gov/15695738/.
Article CAS PubMed Google Scholar
Chandler S, Coates R, Gearing A, Lury J, Wells G, Bone E. Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett. 1995;201(3):223–6.
Article CAS PubMed Google Scholar
Akassoglou K, Bauer J, Kassiotis G, Pasparakis M, Lassmann H, Kollias G, et al. Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: Models for multiple sclerosis with primary oligodendrogliopathy. Am J Pathol. 1998;153(3):801–13 [cited 2021 Jan 2] Available from: https://pubmed.ncbi.nlm.nih.gov/9736029/.
Article CAS PubMed PubMed Central Google Scholar
Márquez-Martín A, Jiménez-Altayó F, Dantas AP, Caracuel L, Planas AM, Vila E. Middle cerebral artery alterations in a rat chronic hypoperfusion model. J Appl Physiol. 2012;112(3):511–8 [cited 2021 Feb 21] Available from: https://pubmed.ncbi.nlm.nih.gov/22096118/.
Article PubMed Google Scholar
Skrobot OA, Black SE, Chen C, DeCarli C, Erkinjuntti T, Ford GA, et al. Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study. Alzheimers Dement. 2018;14(3):280–92 [cited 2021 Jun 16] Available from: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.jalz.2017.09.007.
Article PubMed Google Scholar
Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–38 [cited 2020 Sep 15] Available from: https://pubmed.ncbi.nlm.nih.gov/23867200/.
Article PubMed PubMed Central Google Scholar
Barker R, Wellington D, Esiri MM, Love S. Assessing White matter ischemic damage in dementia patients by measurement of myelin proteins. J Cereb Blood Flow Metab. 2013;33(7):1050–7.
Article CAS PubMed PubMed Central Google Scholar
Masumura M, Hata R, Nagai Y, Sawada T. Oligodendroglial cell death with DNA fragmentation in the white matter under chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats. Neurosci Res. 2001;39(4):401–12.
Article CAS PubMed Google Scholar
Holland PR, Searcy JL, Salvadores N, Scullion G, Chen G, Lawson G, et al. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease. J Cereb Blood Flow Metab. 2015;35(6):1005–14 [cited 2021 May 17] Available from: https://pubmed.ncbi.nlm.nih.gov/25669904/.
Article PubMed PubMed Central Google Scholar
Shibata M, Ohtani R, Ihara M, White TH, Lesions M. Glial Activation in a Novel Mouse Model of Chronic Cerebral Hypoperfusion. Stroke. 2004;35(11):2598–603 [cited 2018 Sep 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15472111.
Article PubMed Google Scholar
Reimer MM, McQueen J, Searcy L, Scullion G, Zonta B, Desmazieres A, et al. Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion. J Neurosci. 2011;31(49):18185–94.
Article CAS PubMed PubMed Central Google Scholar
Barber R, Scheltens P, Gholkar A, Ballard C, McKeith I, Ince P, et al. White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer’s disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry. 1999;67(1):66–72 [cited 2018 Sep 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10369824.
Article CAS PubMed PubMed Central Google Scholar
Gootjes L, Teipel SJ, Zebuhr Y, Schwarz R, Leinsinger G, Scheltens P, et al. Regional Distribution of White Matter Hyperintensities in Vascular Dementia, Alzheimer’s Disease and Healthy Aging. Dement Geriatr Cogn Disord. 2004;18(2):180–8 [cited 2018 Oct 7] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15211074.
Article CAS PubMed Google Scholar
Palesi F, De Rinaldis A, Vitali P, Castellazzi G, Casiraghi L, Germani G, et al. Specific patterns of white matter alterations help distinguishing Alzheimer’s and vascular dementia. Front Neurosci. 2018;12(APR):274.
Article PubMed PubMed Central Google Scholar
Longstreth WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: The cardiovascular health study. Stroke. 1996;27(8):1274–82 [cited 2020 Sep 8] Available from: https://pubmed.ncbi.nlm.nih.gov/8711786/.
Article PubMed Google Scholar
Krishnan MS, O’Brien JT, Firbank MJ, Pantoni L, Carlucci G, Erkinjuntti T, et al. Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study. Int J Geriatr Psychiatry. 2006;21(10):983–9 [cited 2020 Sep 8] Available from: https://pubmed.ncbi.nlm.nih.gov/16955428/.
Article PubMed Google Scholar
Román GC, Kalaria RN. Vascular determinants of cholinergic deficits in Alzheimer disease and vascular dementia. Neurobiol Aging. Elsevier. 2006;27:1769–85.
Article Google Scholar
Gray F, Dubas F, Roullet E, Escourolle R. Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Ann Neurol. 1985;18(1):54–9 [cited 2020 Sep 8] Available from: https://pubmed.ncbi.nlm.nih.gov/4037751/.
Article CAS PubMed Google Scholar
Kim S, Choi SH, Lee YM, Kim MJ, Kim YD, Kim JY, et al. Periventricular white matter hyperintensities and the risk of dementia: a CREDOS study. Int Psychogeriatrics. 2015;27(12):2069–77 [cited 2020 Jun 11] Available from: https://www.cambridge.org/core/product/identifier/S1041610215001076/type/journal_article.
Article Google Scholar
Sulkava R, Erkinjuntti T. Vascular dementia due to cardiac arrhythmias and systemic hypotension. Acta Neurol Scand. 1987;76(2):123–8 [cited 2020 Aug 22] Available from: http://doi.wiley.com/10.1111/j.1600-0404.1987.tb03555.x.
Article CAS PubMed Google Scholar
Bernbaum M, Menon BK, Fick G, Smith EE, Goyal M, Frayne R, et al. Reduced blood flow in normal white matter predicts development of leukoaraiosis. J Cereb Blood Flow Metab. 2015;35(10):1610–5 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/25966951.
Article CAS PubMed PubMed Central Google Scholar
Kalaria RN. Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease. Acta Neuropathologica. Springer Berlin Heidelberg. 2016;131:659–85 [cited 2019 Nov 26] Available from: http://link.springer.com/10.1007/s00401-016-1571-z.
Article Google Scholar
Smith EE, Schneider JA, Wardlaw JM, Greenberg SM. Cerebral microinfarcts: The invisible lesions. The Lancet Neurology. NIH Public Access. 2012;11:272–82 [cited 2020 Oct 26]Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359329/.
Article Google Scholar
Westover MB, Bianchi MT, Yang C, Schneider JA, Greenberg SM. Estimating cerebral microinfarct burden from autopsy samples. Neurology. 2013;80(15):1365–9 [cited 2020 Oct 26] Available from: https://pubmed.ncbi.nlm.nih.gov/23486880/.
Article PubMed PubMed Central Google Scholar
Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LBJ, Tiwari-Woodruff S, et al. Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci. 2009;29(37):11511–22 Available from: https://pubmed.ncbi.nlm.nih.gov/19759299/.
Article CAS PubMed PubMed Central Google Scholar
Brundel M, De Bresser J, Van Dillen JJ, Kappelle LJ, Biessels GJ. Cerebral microinfarcts: A systematic review of neuropathological studies. J Cereb Blood Flow Metab. 2012;32:425–36 [cited 2020 Oct 26] Available from: https://pubmed.ncbi.nlm.nih.gov/22234334/.
Article PubMed PubMed Central Google Scholar
Suter OC, Sunthorn T, Kraftsik R, Straubel J, Darekar P, Khalili K, et al. Cerebral hypoperfusion generates cortical watershed microinfarcts in Alzheimer disease. Stroke. 2002;33(8):1986–92 [cited 2020 Oct 26] Available from: https://pubmed.ncbi.nlm.nih.gov/12154250/.
Article PubMed Google Scholar
Okamoto Y, Yamamoto T, Kalaria RN, Senzaki H, Maki T, Hase Y, et al. Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts. Acta Neuropathol. 2012;123(3):381–94 [cited 2020 Oct 26] Available from: https://pubmed.ncbi.nlm.nih.gov/22170742/.
Article CAS PubMed Google Scholar
Hilal S, Sikking E, Shaik MA, Chan QL, Van Veluw SJ, Vrooman H, et al. Cortical cerebral microinfarcts on 3T MRI: A novel marker of cerebrovascular disease. Neurology. 2016;87(15):1583–90 [cited 2020 Oct 26] Available from: https://n.neurology.org/content/87/15/1583.
Article PubMed Google Scholar
Zhang L, Biessels GJ, Hilal S, Chong JSX, Liu S, Shim HY, et al. Cerebral microinfarcts affect brain structural network topology in cognitively impaired patients. J Cereb Blood Flow Metab. 2021;41(1):105–15 [cited 2021 Jan 19] Available from: https://pubmed.ncbi.nlm.nih.gov/31986957/.
Article PubMed Google Scholar
Auriel E, Edlow BL, Reijmer YD, Fotiadis P, Ramirez-Martinez S, Ni J, et al. Microinfarct disruption of white matter structure: A longitudinal diffusion tensor analysis. Neurology. 2014;83(2):182–8 [cited 2020 Oct 26] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117171/.
Article PubMed PubMed Central Google Scholar
Hinman JD, Lee MD, Tung S, Vinters HV, Thomas Carmichael S. Molecular disorganization of axons adjacent to human lacunar infarcts. Brain. 2015;138(3):736–45 [cited 2020 Oct 26] Available from: https://pubmed.ncbi.nlm.nih.gov/25614025/.
Article PubMed PubMed Central Google Scholar
Hartmann DA, Hyacinth HI, Liao FF, Shih AY. Does pathology of small venules contribute to cerebral microinfarcts and dementia? J Neurochem. Blackwell Publishing Ltd. 2018;144:517–26 [cited 2020 Oct 26] Available from: https://pubmed.ncbi.nlm.nih.gov/28950410/.
CAS Google Scholar
Fein G, Di Sclafani V, Tanabe J, Cardenas V, Weiner MW, Jagust WJ, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology. 2000;55(11):1626–35 [cited 2020 Oct 29] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2733356/.
Article CAS PubMed Google Scholar
van de Pol L, Gertz H-J, Scheltens P, Wolf H. Hippocampal Atrophy in Subcortical Vascular Dementia. Neurodegener Dis. 2011;8(6):465–9 [cited 2020 16] Available from: https://www.karger.com/Article/FullText/326695.
Article PubMed Google Scholar
Vijayakumar A, Vijayakumar A. Comparison of Hippocampal Volume in Dementia Subtypes. ISRN. Radiol. 2013;2013:1–5 [cited 2020 Oct 29] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045526/.
Google Scholar
Kirino T, Tamura A, Sano K. Selective vulnerability of the Hippocampus to ischemia — reversible and irreversible types of ischemic cell damage. Prog Brain Res. 1985;63(C):39–58.
Article CAS PubMed Google Scholar
Hossmann K-A. The Hypoxic Brain. Boston, MA: In Springer; 1999. p. 155–69. [cited 2020 Oct 29] Available from: https://link.springer.com/chapter/10.1007/978-1-4615-4711-2_14
Google Scholar
Pulsinelli WA, Brierley JB. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979;10(3):267–72 [cited 2020 Oct 29] Available from: https://pubmed.ncbi.nlm.nih.gov/37614/.
Article CAS PubMed Google Scholar
Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res. 1982;239(1):57–69 [cited 2020 Oct 29] Available from: https://pubmed.ncbi.nlm.nih.gov/7093691/.
Article CAS PubMed Google Scholar
Beudel M, Leenders KL, de Jong BM. Hippocampus activation related to ‘real-time’ processing of visuospatial change. Brain Res. 2016;1652:204–11.
Article CAS PubMed Google Scholar
Goukasian N, Porat S, Blanken A, Avila D, Zlatev D, Hurtz S, et al. Cognitive Correlates of Hippocampal Atrophy and Ventricular Enlargement in Adults with or without Mild Cognitive Impairment. Dement Geriatr Cogn Dis Extra. 2019;9(2):281–93 [cited 2020 Sep 16] Available from: https://www.karger.com/Article/FullText/490044.
Article PubMed PubMed Central Google Scholar
Laczó J, Andel R, Nedelska Z, Vyhnalek M, Vlcek K, Crutch S, et al. Exploring the contribution of spatial navigation to cognitive functioning in older adults. Neurobiol Aging. 2017;51:67–70 [cited 2020 Sep 16] Available from: https://pubmed.ncbi.nlm.nih.gov/28039765/.
Article PubMed Google Scholar
Sinclair LI, Tayler HM, Love S. Synaptic protein levels altered in vascular dementia. Neuropathol Appl Neurobiol. 2015;41(4):533–43 [cited 2020 Oct 29] Available from: https://pubmed.ncbi.nlm.nih.gov/25559750/.
Article CAS PubMed PubMed Central Google Scholar
Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, et al. National Institute of Neurological Disorders and Stroke–Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards. Stroke. 2006;37(9):2220–41 [cited 2019 Nov 26] Available from: http://www.ncbi.nlm.nih.gov/pubmed/16917086.
Article PubMed Google Scholar
Voss SE, Bullock RA. Executive Function: The Core Feature of Dementia? Dement Geriatr Cogn Disord. 2004;18(2):207–16 [cited 2020 Nov 1] Available from: https://www.karger.com/Article/FullText/79202.
Article PubMed Google Scholar
Moorhouse P, Song X, Rockwood K, Black S, Kertesz A, Gauthier S, et al. Executive dysfunction in vascular cognitive impairment in the consortium to investigate vascular impairment of cognition study. J Neurol Sci. 2010;288(1–2):142–6.
Article PubMed Google Scholar
Kramer JH, Reed BR, Mungas D, Weiner MW, Chui HC. Executive dysfunction in subcortical ischaemic vascular disease. J Neurol Neurosurg Psychiatry. 2002;72(2):217–20 [cited 2020 Nov 1] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1737728/.
Article CAS PubMed PubMed Central Google Scholar
Benjamin P, Lawrence AJ, Lambert C, Patel B, Chung AW, Mackinnon AD, et al. Strategic lacunes and their relationship to cognitive impairment in cerebral small vessel disease. NeuroImage Clin. 2014;4:828–37.
Article PubMed PubMed Central Google Scholar
Salmon DP, Bondi MW. Neuropsychological assessment of dementia. Annual Review of Psychology. NIH Public Access. 2009;60:257–82 [cited 2020 Nov 7] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864104/.
Article Google Scholar
Bentham PW, Jones S, Hodges JR. A comparison of semantic memory in vascular dementia and dementia of Alzheimer’s type. Int J Geriatr Psychiatry. 1997;12(5):575–80 [cited 2020 Nov 7] Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291099-1166%28199705%2912%3A5%3C575%3A%3AAID-GPS566%3E3.0.CO%3B2-N.
Article CAS PubMed Google Scholar
Graham NL, Emery T, Hodges JR. Distinctive cognitive profiles in Alzheimer’s disease and subcortical vascular dementia. J Neurol Neurosurg Psychiatry. 2004;75(1):61–71 [cited 2020 Nov 7] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757469/.
CAS PubMed PubMed Central Google Scholar
Vuorinen E, Laine M, Rinne J. Common pattern of language impairment in vascular dementia and in Alzheimer disease. Alzheimer Dis Assoc Disord. 2000;14(2):81–6 [cited 2020 Nov 7] Available from: https://pubmed.ncbi.nlm.nih.gov/10850746/.
Article CAS PubMed Google Scholar
Ricker JH, Keenan PA, Jacobson MW. Visuoperceptual-spatial ability and visual memory in vascular dementia and dementia of the Alzheimer type. Neuropsychologia. 1994;32(10):1287–96.
Article CAS PubMed Google Scholar
Gyanwali B, Venketasubramanian N, Chen C, Hilal S. Effects of cerebral small vessels disease on brain perfusion in a memory clinic population. J Cereb Blood Flow Metab. 2019;39:135 [cited 2021 Jan 19] Available from: https://research.vumc.nl/en/publications/effects-of-cerebral-small-vessels-disease-on-brain-perfusion-in-a.
Google Scholar
Stefaniak J, O’brien J. Imaging of neuroinflammation in dementia: A review. J Neurol Neurosurg Psychiatry. BMJ Publishing Group Ltd. 2016;87:21–8 [cited 2021 Sep 2] Available from: https://jnnp-bmj-com.libproxy1.nus.edu.sg/content/87/1/21.
Google Scholar
Passamonti L, Tsvetanov KA, Jones PS, Bevan-Jones WR, Arnold R, Borchert RJ, et al. Neuroinflammation and functional connectivity in Alzheimer’s disease: Interactive influences on cognitive performance. J Neurosci. 2019;39(36):7218–26 [cited 2021 Sep 2] Available from: https://www.jneurosci.org/content/39/36/7218.
Article CAS PubMed PubMed Central Google Scholar
Ng A, Tam WW, Zhang MW, Ho CS, Husain SF, McIntyre RS, et al. IL-1β, IL-6, TNF- α and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta-Analysis. Sci Rep. 2018;8(1):1–12 [cited 2021 Sep 4] Available from: https://www.nature.com/articles/s41598-018-30487-6.
Article Google Scholar
Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol. 2002;52(2):168–74 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/12210786.
Article PubMed Google Scholar
Ravaglia G, Forti P, Maioli F, Chiappelli M, Montesi F, Tumini E, et al. Blood inflammatory markers and risk of dementia: The Conselice Study of Brain Aging. Neurobiol Aging. 2007;28(12):1810–20 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/17011077.
Article CAS PubMed Google Scholar
Chen A, Oakley AE, Monteiro M, Tuomela K, Allan LM, Mukaetova-Ladinska EB, et al. Multiplex analyte assays to characterize different dementias: Brain inflammatory cytokines in poststroke and other dementias. Neurobiol Aging. 2016;38:56–67 [cited 2021 Sep 4] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759608/.
Article PubMed PubMed Central Google Scholar
Mulugeta E, Molina-Holgado F, Elliott MS, Hortobagyi T, Perry R, Kalaria RN, et al. Inflammatory mediators in the frontal lobe of patients with mixed and vascular dementia. Dement Geriatr Cogn Disord. 2008;25(3):278–86 [cited 2021 Apr 28] Available from: https://pubmed.ncbi.nlm.nih.gov/18303264/.
Article CAS PubMed Google Scholar
Yamada K, Kono K, Umegaki H, Yamada K, Iguchi A, Fukatsu T, et al. Decreased interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia. Neurosci Lett. 1995;186(2–3):219–21 [cited 2021 Sep 4] Available from: https://pubmed.ncbi.nlm.nih.gov/7777201/.
Article CAS PubMed Google Scholar
Kim SM, Song J, Kim S, Han C, Park MH, Koh Y, et al. Identification of peripheral inflammatory markers between normal control and Alzheimer’s disease. BMC Neurol. 2011;11:51 [cited 2021 Sep 4] Available from: https://pubmed.ncbi.nlm.nih.gov/21569380/.
Article CAS PubMed PubMed Central Google Scholar
Paganelli R, Di Iorio A, Patricelli L, Ripani F, Sparvieri E, Faricelli R, et al. Proinflammatory cytokines in sera of elderly patients with dementia: Levels in vascular injury are higher than those of mild-moderate Alzheimer’s disease patients. Exp Gerontol. 2002;37(2–3):257–63 [cited 2021 Apr 28] Available from: https://pubmed.ncbi.nlm.nih.gov/11772511/.
Article CAS PubMed Google Scholar
Cuello AC. Early and Late CNS Inflammation in Alzheimer’s Disease: Two Extremes of a Continuum? Trends Pharmacol Sci. 2017;38:956–66 [cited 2021 Sep 6] Available from: https://pubmed.ncbi.nlm.nih.gov/28867259/.
Article CAS PubMed Google Scholar
Koelman L, Pivovarova-Ramich O, Pfeiffer AFH, Grune T, Aleksandrova K. Cytokines for evaluation of chronic inflammatory status in ageing research: Reliability and phenotypic characterisation. Immun Ageing. 2019;16(1):1–12 [cited 2021 Sep 6] Available from: https://immunityageing.biomedcentral.com/articles/10.1186/s12979-019-0151-1.
Article Google Scholar
Gomez-Nicola D, Boche D. Post-mortem analysis of neuroinflammatory changes in human Alzheimer’s disease. Alzheimer’s Res Ther. 2015;7(1):42 [cited 2021 Sep 6] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405851/.
Article Google Scholar
Aziz N. Measurement of circulating cytokines and immune-activation markers by multiplex technology in the clinical setting: What are wereally measuring? For Immunopathol Dis Therap. 2015;6(1–2):19–22 [cited 2021 Sep 6] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5345938/.
PubMed PubMed Central Google Scholar
Malaguarnera L, Motta M, Di Rosa M, Anzaldi M, Malaguarnera M. Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer’s disease and vascular dementia. Neuropathology. 2006;26(4):307–12.
Article PubMed Google Scholar
Cacabelos R, Alvarez XA, Fernandez-Novoa L, Franco A, Mangues R, Pellicer A, et al. Brain interleukin-1β in Alzheimer’s disease and vascular dementia. Methods Find Exp Clin Pharmacol. 1994;16(2):141–51 [cited 2021 Sep 2] Available from: https://pubmed.ncbi.nlm.nih.gov/8007743/.
CAS PubMed Google Scholar
Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell Cell Press. 2014;157:1013–22. [cited 2021 Jan 12] Available from:. https://doi.org/10.1016/j.cell.2014.04.007.
Article CAS Google Scholar
Patel MN, Carroll RG, Galván-Peña S, Mills EL, Olden R, Triantafilou M, et al. Inflammasome priming in sterile Inflammatory disease. Trends Mol Med. 2017;23(2):165–80.
Article CAS PubMed Google Scholar
Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479(7371):117–21 [cited 2016 Oct 8] Available from: http://www.ncbi.nlm.nih.gov/pubmed/22002608.
Article CAS PubMed Google Scholar
He Q, You H, Li X-M, Liu T-H, Wang P, Wang B-E. HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 by activation of p38 MAPK and NF-κB through receptors for advanced Glycation end-products in macrophages. Asian Pacific J Cancer Prev. 2012;13(4):1365–70.
Article Google Scholar
Fann DYW, Lim YA, Cheng YL, Lok KZ, Chunduri P, Baik SH, et al. Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. Mol Neurobiol. 2018;55(2):1082–96 [cited 2021 Jan 21] Available from: https://pubmed.ncbi.nlm.nih.gov/28092085/.
Article CAS PubMed Google Scholar
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009;183(2):787–91.
Article CAS PubMed Google Scholar
Fann DY-W, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4(9):e790.
Article CAS PubMed Google Scholar
Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287(43):36617–22.
Article CAS PubMed PubMed Central Google Scholar
Rubartelli A. DAMP-mediated activation of NLRP3-Inflammasome in Brain sterile inflammation: the fine line between healing and Neurodegeneration. Front Immunol. 2014;5:99.
Article PubMed PubMed Central Google Scholar
Poh L, Kang SW, Baik SH, Ng GYQ, She DT, Balaganapathy P, et al. Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke. Brain Behav Immun. 2019;75:34–47 [cited 2018 Sep 13] Available from: http://www.ncbi.nlm.nih.gov/pubmed/30195027.
Article CAS PubMed Google Scholar
Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458(7237):514–8 [cited 2021 Apr 28] Available from: https://pubmed.ncbi.nlm.nih.gov/19158675/.
Article CAS PubMed PubMed Central Google Scholar
Man SM, Tourlomousis P, Hopkins L, Monie TP, Fitzgerald KA, Bryant CE. Salmonella Infection Induces Recruitment of Caspase-8 to the Inflammasome To Modulate IL-1β Production. J Immunol. 2013;191(10):5239–46 [cited 2021 Feb 26] Available from: https://pubmed.ncbi.nlm.nih.gov/24123685/.
Article CAS PubMed Google Scholar
Gurung P, Kanneganti T-D. Novel roles for caspase-8 in IL-1β and inflammasome regulation. Am J Pathol. 2015;185(1):17–25 [cited 2019 Jul 19] Available from: http://www.ncbi.nlm.nih.gov/pubmed/25451151.
Article CAS PubMed PubMed Central Google Scholar
Sagulenko V, Vitak N, Vajjhala PR, Vince JE, Stacey KJ. Caspase-1 is an apical Caspase leading to Caspase-3 cleavage in the AIM2 Inflammasome response, independent of Caspase-8. J Mol Biol. 2018;430(2):238–47.
Article CAS PubMed Google Scholar
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526(7575):660–5.
Article CAS PubMed Google Scholar
Sarhan J, Liu BC, Muendlein HI, Li P, Nilson R, Tang AY, et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc Natl Acad Sci. 2018;115(46):E10888–97.
Article CAS PubMed PubMed Central Google Scholar
Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666–71 [cited 2019 Jul 19] Available from: http://www.nature.com/articles/nature15541.
Article CAS PubMed Google Scholar
Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–8.
Article CAS PubMed PubMed Central Google Scholar
Pétrilli V, Papin S, Dostert C, Mayor A, Martinon F, Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007;14(9):1583–9 [cited 2021 Mar 11] Available from: https://pubmed.ncbi.nlm.nih.gov/17599094/.
Article PubMed Google Scholar
Rühl S, Broz P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K + efflux. Eur J Immunol. 2015;45(10):2927–36 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/26173909.
Article PubMed Google Scholar
Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science. 2016;352(6290):1232–6.
Article CAS PubMed PubMed Central Google Scholar
Ting JP-Y, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, et al. The NLR gene family: a standard nomenclature. Immunity. 2008;28(3):285–7.
Article CAS PubMed PubMed Central Google Scholar
Jha S, Ting JP-Y. Inflammasome-associated nucleotide-binding domain, leucine-rich repeat proteins and inflammatory diseases. J Immunol. 2009;183(12):7623–9 [cited 2016 Mar 11] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666034/.
Article CAS PubMed Google Scholar
Proell M, Gerlic M, Mace PD, Reed JC, Riedl SJ. The CARD plays a critical role in ASC foci formation and inflammasome signalling. Biochem J. 2013;449(3):613–21 [cited 2016 Feb 18] Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3966062&tool=pmcentrez&rendertype=abstract.
Article CAS PubMed Google Scholar
Jin T, Perry A, Smith P, Jiang J, Xiao TS. Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem. 2013;288(19):13225–35.
Article CAS PubMed PubMed Central Google Scholar
Gong Q, Robinson K, Xu C, Huynh PT, Chong KHC, Tan EYJ, et al. Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8. Nat Commun. 2021;12(1):1–15. [cited 2021 Mar 20] Available from:. https://doi.org/10.1038/s41467-020-20319-5.
Article CAS Google Scholar
Finger JN, Lich JD, Dare LC, Cook MN, Brown KK, Duraiswamis C, et al. Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J Biol Chem. 2012;287(30):25030–7 [cited 2021 Mar 20] Available from: https://pubmed.ncbi.nlm.nih.gov/22665479/.
Article CAS PubMed PubMed Central Google Scholar
Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 2019;570(7761):338–43 [cited 2021 May 17] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774351/.
Article CAS PubMed PubMed Central Google Scholar
Matyszewski M, Zheng W, Lueck J, Antiochos B, Egelman EH, Sohn J. Cryo-EM structure of the NLRC4CARD filament provides insights into how symmetric and asymmetric supramolecular structures drive inflammasome assembly. J Biol Chem. 2018;293(52):20240–8 [cited 2021 May 17] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311515/.
Article CAS PubMed PubMed Central Google Scholar
Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science. 2009;323(5917):1057–60.
Article CAS PubMed Google Scholar
Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell. 2014;156(6):1193–206 [cited 2016 Jan 15] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000066/.
Article CAS PubMed PubMed Central Google Scholar
Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell. 1998;92(4):501–9 [cited 2016 Oct 8] Available from: http://www.ncbi.nlm.nih.gov/pubmed/9491891.
Article CAS PubMed Google Scholar
Boucher D, Monteleone M, Coll RC, Chen KW, Ross CM, Teo JL, et al. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity. J Exp Med. 2018;215(3):827–40 [cited 2019 Jul 19] Available from: http://www.ncbi.nlm.nih.gov/pubmed/29432122.
Article CAS PubMed PubMed Central Google Scholar
Blanchard H, Kodandapani L, Mittl PRE, Di Marco S, Krebs JF, Wu JC, et al. The three-dimensional structure of caspase-8: An initiator enzyme in apoptosis. Structure. 1999;7(9):1125–33 [cited 2021 Feb 24] Available from: https://pubmed.ncbi.nlm.nih.gov/10508784/.
Article CAS PubMed Google Scholar
Case CL, Kohler LJ, Lima JB, Strowig T, Zoete MRD, Flavell RA, et al. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad Sci U S A. 2013;110(5):1851–6 [cited 2021 Feb 24] Available from: https://pubmed.ncbi.nlm.nih.gov/23307811/.
Article CAS PubMed PubMed Central Google Scholar
Huang X, Feng Y, Xiong G, Whyte S, Duan J, Yang Y, et al. Caspase-11, a specific sensor for intracellular lipopolysaccharide recognition, mediates the non-canonical inflammatory pathway of pyroptosis. Cell Biosci BioMed Central Ltd. 2019;9:31 [cited 2021 Feb 24] Available from: https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-019-0292-0.
Article Google Scholar
Liao K-C, Mogridge J. Activation of the Nlrp1b inflammasome by reduction of cytosolic ATP. Infect Immun. 2013;81(2):570–9.
Article CAS PubMed PubMed Central Google Scholar
Lee G-S, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012;492(7427):123–7.
Article CAS PubMed PubMed Central Google Scholar
Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G. K+ efflux is the common trigger of NLRP3 Inflammasome activation by bacterial toxins and particulate matter. Immunity. 2013;38(6):1142–53.
Article PubMed PubMed Central Google Scholar
Nägga K, Hansson O, Van Westen D, Minthon L, Wennström M. Increased levels of hyaluronic acid in cerebrospinal fluid in patients with vascular dementia. J Alzheimer’s Dis. 2014;42(4):1435–41 [cited 2021 Feb 24] Available from: https://pubmed.ncbi.nlm.nih.gov/25024336/.
Article Google Scholar
Markus HS. Cerebral perfusion and stroke. J Neurology, Neurosurgery and Psychiatry. BMJ Publishing Group Ltd. 2004;75:353–61 [cited 2021 Sep 9] Available from: https://jnnp.bmj.com/content/75/3/353.
Article CAS Google Scholar
Paik S, Kim JK, Silwal P, Sasakawa C, Jo EK. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cellular and Molecular Immunology. Nature Publishing Group. 2021;18:1141–60 [cited 2021 Sep 9] Available from: https://www.nature.com/articles/s41423-021-00670-3.
Article CAS Google Scholar
Whyte-Fagundes P, Zoidl G. Mechanisms of pannexin1 channel gating and regulation. Biochimica et Biophysica Acta – Biomembranes. Elsevier. 2018;1860:65–71.
Article CAS Google Scholar
Silverman WR, de Rivero Vaccari JP, Locovei S, Qiu F, Carlsson SK, Scemes E, et al. The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J Biol Chem. 2009;284(27):18143–51 [cited 2021 Sep 10] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709345/.
Article CAS PubMed PubMed Central Google Scholar
Xu Z, Chen ZM, Wu X, Zhang L, Cao Y, Zhou P. Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation. Front Immunol. Frontiers Media SA. 2020;11 [cited 2021 Sep 9] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793832/.
Tapia-Abellan A, Angosto-Bazarra D, Alarcon-Vila C, Baños MC, Hafner-Bratkovič I, Oliva B, et al. Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation. Sci Adv. 2021;7(38):4468–83 [cited 2021 Sep 17];in press Available from: https://www.science.org/doi/abs/10.1126/sciadv.abf4468.
Article Google Scholar
Li H, Wang J, Wang P, Rao Y, Chen L. Resveratrol Reverses the Synaptic Plasticity Deficits in a Chronic Cerebral Hypoperfusion Rat Model. J Stroke Cerebrovasc Dis. 2016;25(1):122–8 [cited 2021 Sep 9] Available from: https://pubmed.ncbi.nlm.nih.gov/26456198/.
Article CAS PubMed Google Scholar
Peng K, Liu L, Wei D, Lv Y, Wang G, Xiong W, et al. P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation. Int J Mol Med. 2015;35(5):1179–88 [cited 2021 Sep 11] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380202/.
Article CAS PubMed PubMed Central Google Scholar
Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundbäck P, et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012;488(7413):670–4 [cited 2021 Sep 11] Available from: https://pubmed.ncbi.nlm.nih.gov/22801494/.
Article CAS PubMed PubMed Central Google Scholar
Lane T, Flam B, Lockey R, Kolliputi N. TXNIP shuttling: missing link between oxidative stress and inflammasome activation, vol. 4. MAR: Frontiers in Physiology. Frontiers; 2013. p. 50
Google Scholar
Ye X, Zuo D, Yu L, Zhang L, Tang J, Cui C, et al. ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia. Biochem Biophys Res Commun. 2017;485(2):499–505 [cited 2021 Sep 9] Available from: https://pubmed.ncbi.nlm.nih.gov/28202418/.
Article CAS PubMed Google Scholar
Han Y, Xu X, Tang C, Gao P, Chen X, Xiong X, et al. Reactive oxygen species promote tubular injury in diabetic nephropathy: The role of the mitochondrial ros-txnip-nlrp3 biological axis. Redox Biol. 2018;16:32–46 [cited 2021 Sep 9] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842313/.
Article CAS PubMed PubMed Central Google Scholar
Abais JM, Xia M, Li G, Chen Y, Conley SM, Gehr TWB, et al. Nod-like receptor protein 3 (NLRP3) inflammasome activation and podocyte injury via thioredoxin-interacting protein (TXNIP) during hyperhomocysteinemia. J Biol Chem. 2014;289(39):27159–68 [cited 2021 Sep 9] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175351/.
Article CAS PubMed PubMed Central Google Scholar
Saxena AK, Abdul-Majeed SS, Gurtu S, WMY M. Investigation of redox status in chronic cerebral hypoperfusion-induced neurodegeneration in rats. Appl Transl Genomics. 2015;5:30–2 [cited 2021 Sep 9] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745367/.
Article Google Scholar
Du SQ, Wang XR, Zhu W, Ye Y, Yang JW, Ma SM, et al. Acupuncture inhibits TXNIP-associated oxidative stress and inflammation to attenuate cognitive impairment in vascular dementia rats. CNS Neurosci Ther. 2018;24(1):39–46 [cited 2021 Sep 9] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489958/.
Article CAS PubMed Google Scholar
Zhang L, Chen S, Ruan J, Wu J, Tong AB, Yin Q, et al. Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization. Science. 2015;350(6259):404–9 [cited 2021 Feb 25] Available from: https://pubmed.ncbi.nlm.nih.gov/26449474/.
Article CAS PubMed PubMed Central Google Scholar
Freeman L, Guo H, David CN, Brickey WJ, Jha S, Ting JP-Y. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J Exp Med. 2017;214(5):1351–70.
Article CAS PubMed PubMed Central Google Scholar
Scholz H, Eder C. Lysophosphatidylcholine activates caspase-1 in microglia via a novel pathway involving two inflammasomes. J Neuroimmunol. 2017;310:107–10.
Article CAS PubMed Google Scholar
Ismaeel S, Qadri A. ATP Release Drives Inflammation with Lysophosphatidylcholine. ImmunoHorizons. 2021;5(4):219–33 [cited 2021 Sep 10] Available from: https://www.immunohorizons.org/content/5/4/219.
Article CAS PubMed Google Scholar
Ying Y. Sphingosine kinase inhibition ameliorates chronic hypoperfusion-induced white matter lesions. [Singapore]: National University of Singapore; 2016.
Google Scholar
Furman D, Chang J, Lartigue L, Bolen CR, Haddad F, Gaudilliere B, et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med. 2017;23(2):174–84.
Article CAS PubMed PubMed Central Google Scholar
Wang B, Yin Q. AIM2 inflammasome activation and regulation: a structural perspective. J Struct Biol. 2017;200(3):279–82.
Article CAS PubMed PubMed Central Google Scholar
Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, et al. Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 Inflammasome and IFI16 receptor. Immunity. 2012;36(4):561–71.
Article CAS PubMed PubMed Central Google Scholar
Lénárt N, Brough D, Dénes Á. Inflammasomes link vascular disease with neuroinflammation and brain disorders. J Cereb Blood Flow Metab. SAGE Publications. 2016;36:1668–85 [cited 2019 Jan 9] Available from: http://www.ncbi.nlm.nih.gov/pubmed/27486046.
Article Google Scholar
Bae JH, Jo SI, Kim SJ, Lee JM, Jeong JH, Kang JS, et al. Circulating cell-free mtDNA contributes to AIM2 Inflammasome-mediated Chronic inflammation in patients with type 2 diabetes. Cells. 2019;8(4):328.
Article CAS PubMed Central Google Scholar
Tomimoto H, Ihara M, Wakita H, Ohtani R, Lin J-X, Akiguchi I, et al. Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol. 2003;106(6):527–34.
Article CAS PubMed Google Scholar
Kim MS, Bang JH, Lee J, Han JS, Baik TG, Jeon WK. Ginkgo biloba L. extract protects against chronic cerebral hypoperfusion by modulating neuroinflammation and the cholinergic system. Phytomedicine. 2016;23(12):1356–64 [cited 2021 Sep 10] Available from: https://pubmed.ncbi.nlm.nih.gov/27765355/.
Article CAS PubMed Google Scholar
Sirois CM, Jin T, Miller AL, Bertheloot D, Nakamura H, Horvath GL, et al. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J Exp Med. 2013;210(11):2447–63.
Article CAS PubMed PubMed Central Google Scholar
Lechtenberg BC, Mace PD, Riedl SJ. Structural mechanisms in NLR inflammasome signaling. Curr Opin Structl Biol. Elsevier Ltd. 2014;29:17–25 [cited 2021 May 8] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268015/.
Article CAS Google Scholar
Hoss F, Rodriguez-Alcazar JF, Latz E. Assembly and regulation of ASC specks. Cell Mol Life Sci. 2017;74(7):1211–29.
Article CAS PubMed Google Scholar
Van Opdenbosch N, Gurung P, Vande Walle L, Fossoul A, Kanneganti TD, Lamkanfi M. Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation. Nat Commun. 2014;5. [cited 2021 Feb 25] Available from: https://pubmed.ncbi.nlm.nih.gov/24492532/
Rodgers MA, Bowman JW, Fujita H, Orazio N, Shi M, Liang Q, et al. The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med. 2014;211(7):1333–47.
Article CAS PubMed PubMed Central Google Scholar
Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL, Lamkanfi M, et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature. 2012;490(7421):539–42.
Article CAS PubMed Google Scholar
Lu A, Li Y, Yin Q, Ruan J, Yu X, Egelman E, et al. Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2. Cell Discov. 2015;1(1):1 [cited 2021 May 17] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646227/.
Article Google Scholar
Schroder K, Tschopp J. The Inflammasomes. Cell. 2010;140:821–32 [cited 2021 Feb 26] Available from: https://pubmed.ncbi.nlm.nih.gov/20303873/.
Article CAS PubMed Google Scholar
Antonopoulos C, Russo HM, El Sanadi C, Martin BN, Li X, Kaiser WJ, et al. Caspase-8 as an effector and regulator of NLRP3 inflammasome signaling. J Biol Chem. 2015;290(33):20167–84 [cited 2021 Feb 26] Available from: http://www.jbc.org/article/S002192582042157X/fulltext.
Article CAS PubMed PubMed Central Google Scholar
Vajjhala PR, Lu A, Brown DL, Pang SW, Sagulenko V, Sester DP, et al. The inflammasome adaptor ASC induces procaspase-8 death effector domain filaments. J Biol Chem. 2015;290(49):29217–30 [cited 2021 Feb 26] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705927/.
Article CAS PubMed PubMed Central Google Scholar
Chu LH, Indramohan M, Ratsimandresy RA, Gangopadhyay A, Morris EP, Monack DM, et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat Commun. 2018;9(1):1–16.
Article Google Scholar
Ross C, Chan AH, Von Pein J, Boucher D, Schroder K. Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome. Life Sci Alliance. 2018 ;1(6). [cited 2021 Feb 27] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284101/
Bian ZM, Elner SG, Yoshida A, Kunkel SL, Su J, Elner VM. Activation of p38, ERK1/2 and NIK pathways is required for IL-1β and TNF-α-induced chemokine expression in human retinal pigment epithelial cells. Exp Eye Res. 2001;73(1):111–21.
Article CAS PubMed Google Scholar
Emsley HCA, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005;76(10):1366–72 [cited 2021 Jan 22] Available from: https://pubmed.ncbi.nlm.nih.gov/16170078/.
Article CAS PubMed PubMed Central Google Scholar
Bethea JR, Gillespie GY, Benveniste EN. Interleukin-1β induction of TNF-α gene expression: Involvement of protein kinase C. J Cell Physiol. 1992;152(2):264–73 [cited 2021 Jan 21] Available from: https://pubmed.ncbi.nlm.nih.gov/1639861/.
Article CAS PubMed Google Scholar
Wang X, Feuerstein GZ, Gu JL, Lysko PG, Yue TL. Interleukin-1β induces expression of adhesion molecules in human vascular smooth muscle cells and enhances adhesion of leukocytes to smooth muscle cells. Atherosclerosis. 1995;115(1):89–98 [cited 2021 Jan 21] Available from: https://pubmed.ncbi.nlm.nih.gov/7545398/.
Article CAS PubMed Google Scholar
Yata K, Nishimura Y, Unekawa M, Tomita Y, Suzuki N, Tanaka T, et al. In vivo imaging of the mouse neurovascular unit under chronic cerebral hypoperfusion. Stroke. 2014;45(12):3698–703 [cited 2021 Nov 12] Available from: https://www.ahajournals.org/doi/abs/10.1161/strokeaha.114.005891.
Article PubMed Google Scholar
Wakita H, Tomimoto H, Akiguchi I, Kimura J. Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study. Acta Neuropathol. 1994;87(5):484–92 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/8059601.
Article CAS PubMed Google Scholar
Man SM, Kanneganti T-D. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol. 2016;16(1):7–21.
Article CAS PubMed Google Scholar
Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 1999;6(2):99–104 [cited 2016 Jan 28] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10200555.
Article CAS PubMed Google Scholar
Lamkanfi M, Kanneganti T-D, Van Damme P, Vanden Berghe T, Vanoverberghe I, Vandekerckhove J, et al. Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. Mol Cell Proteomics. 2008;7(12):2350–63.
Article CAS PubMed PubMed Central Google Scholar
Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, et al. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol. 2000;149(3):613–22 [cited 2016 Oct 8] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10791975.
Article CAS PubMed PubMed Central Google Scholar
Feng S, Fox D, Man SM. Mechanisms of Gasdermin Family Members in Inflammasome Signaling and Cell Death. J Mol Biol. 2018;430(18):3068–80 [cited 2019 Jul 18] Available from: http://www.ncbi.nlm.nih.gov/pubmed/29990470.
Article CAS PubMed Google Scholar
Garrido C, Galluzzi L, Brunet M, Puig PE, Didelot C, Kroemer G. Mechanisms of cytochrome c release from mitochondria. Vol. 13, Cell Death and Differentiation. Nature Publishing Group; 2006. p. 1423–33.
Google Scholar
Mascarenhas DPA, Cerqueira DM, Pereira MSF, Castanheira FVS, Fernandes TD, Manin GZ, et al. Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome. Seifert HS. PLOS Pathog. 2017;13(8):e1006502.
Article PubMed PubMed Central Google Scholar
Kim SU, de Vellis J. Microglia in health and disease. J Neurosci Res. 2005;81(3):302–13 [cited 2016 Jan 7] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15954124.
Article CAS PubMed Google Scholar
Barreto G, White RE, Ouyang Y, Xu L, Giffard RG. Astrocytes: targets for neuroprotection in stroke. Cent Nerv Syst Agents Med Chem. 2011;11(2):164–73 [cited 2020 Jun 7] Available from: http://www.ncbi.nlm.nih.gov/pubmed/21521168.
Article CAS PubMed PubMed Central Google Scholar
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. J Neurosci. 2014;34(36):11929 [cited 2020 Apr 30] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152602/.
Article CAS PubMed PubMed Central Google Scholar
Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol. 2013;2013:746068.
Article PubMed PubMed Central Google Scholar
Stratoulias V, Venero JL, Tremblay M, Joseph B. Microglial subtypes: diversity within the microglial community. EMBO J. 2019;38(17) [cited 2021 Sep 13] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717890/.
Su S-H, Wu Y-F, Lin Q, Wang D-P, Hai J. URB597 protects against NLRP3 inflammasome activation by inhibiting autophagy dysfunction in a rat model of chronic cerebral hypoperfusion. J Neuroinflammation. 2019;16(1):260 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/31815636.
Article CAS PubMed PubMed Central Google Scholar
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7 [cited 2021 Feb 2] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404890/.
Article CAS PubMed PubMed Central Google Scholar
Liddelow SA, Barres BA. Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity. 2017;46:957–67 [cited 2021 Sep 13] Available from: https://pubmed.ncbi.nlm.nih.gov/28636962/.
Article CAS PubMed Google Scholar
Sofroniew MV. Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity. Trends Immunol. 2020;41:758–70 [cited 2021 Sep 13] Available from: https://pubmed.ncbi.nlm.nih.gov/32819810/.
Article CAS PubMed PubMed Central Google Scholar
Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. 2016;323:170–82 [cited 2021 Sep 13] Available from: https://pubmed.ncbi.nlm.nih.gov/25595973/.
Article PubMed Google Scholar
Kaiser M, Maletzki I, Hülsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F, et al. Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the SOD1 (G93A) transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem. 2006;99(3):900–12 [cited 2021 Sep 13] Available from: https://pubmed.ncbi.nlm.nih.gov/16925593/.
Article CAS PubMed Google Scholar
Li K, Li J, Zheng J, Qin S. Reactive astrocytes in neurodegenerative diseases. Aging Dis. JKL International LLC. 2019;10:664–75 [cited 2021 Sep 13] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538217/.
Article CAS Google Scholar
Zeis T, Allaman I, Gentner M, Schroder K, Tschopp J, Magistretti PJ, et al. Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling. Brain Behav Immun. 2015;48:313–25 [cited 2021 Sep 14] Available from: https://pubmed.ncbi.nlm.nih.gov/25937052/.
Article CAS PubMed Google Scholar
Lau LT, ACH Y. Astrocytes produce and release interleukin-1, interleukin-6, tumor necrosis factor alpha and interferon-gamma following traumatic and metabolic injury. J Neurotrauma. 2001;18(3):351–9 [cited 2021 Sep 14] Available from: https://pubmed.ncbi.nlm.nih.gov/11284554/.
Article CAS PubMed Google Scholar
Candelario-Jalil E, Yang Y, Rosenberg GA. Diverse roles of matrix metalloproteinases and tissue inhibitors of metalloproteinases in neuroinflammation and cerebral ischemia. Neuroscience. 2009;158(3):983–94.
Article CAS PubMed Google Scholar
Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA. Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab. 2007;27(4):697–709 [cited 2021 May 17] Available from: https://pubmed.ncbi.nlm.nih.gov/16850029/.
Article CAS PubMed Google Scholar
Xie Z, Singh M, Singh K. Differential regulation of matrix metalloproteinase-2 and -9 expression and activity in adult rat cardiac fibroblasts in response to interleukin-1β. J Biol Chem. 2004;279(38):39513–9 [cited 2021 Feb 1] Available from: https://pubmed.ncbi.nlm.nih.gov/15269222/.
Article CAS PubMed Google Scholar
Cheng CY, Kuo CT, Lin CC, Hsieh HL, Yang CM. IL-1 induces expression of matrix metalloproteinase-9 and cell migration via a c-Src-dependent, growth factor receptor transactivation in A549 cells. Br J Pharmacol. 2010;160(7):1595–610 [cited 2021 Feb 1] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936833/.
Article CAS PubMed PubMed Central Google Scholar
Rigor RR, Beard RS, Litovka OP, Yuan SY. Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium. Am J Physiol Physiol. 2012;302(10):C1513–22 [cited 2021 Jan 8] Available from: https://www.physiology.org/doi/10.1152/ajpcell.00371.2011.
Article CAS Google Scholar
Hayashi M, Luo Y, Laning J, Strieter RM, Dorf ME. Production and function of monocyte chemoattractant protein-1 and other beta-chemokines in murine glial cells. J Neuroimmunol. 1995;60(1–2):143–50 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/7642742.
Article CAS PubMed Google Scholar
Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, et al. Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol - Hear Circ Physiol. 2005;289(2 58–2):558–68 [cited 2021 Jan 8] Available from: https://journals.physiology.org/doi/full/10.1152/ajpheart.01275.2004?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org.
Article Google Scholar
Turner RJ, Sharp FR. Implications of MMP9 for blood brain barrier disruption and hemorrhagic transformation following ischemic stroke. Vol. 10, Frontiers in Cellular Neuroscience. Frontiers Research Foundation; 2016 [cited 2021 Jan 8]. p. 56. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777722/
Google Scholar
Zhang DD, Jin C, Zhang YT, Gan XD, Zou MJ, Wang YY, et al. A novel IL-1RA-PEP fusion protein alleviates blood-brain barrier disruption after ischemia-reperfusion in male rats. J Neuroinflammation. 2018;15(1):16 [cited 2021 Jan 8] Available from: https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-018-1058-z.
Article PubMed PubMed Central Google Scholar
Liang Y, Song P, Chen W, Xie X, Luo R, Su J, et al. Inhibition of Caspase-1 Ameliorates Ischemia-Associated Blood-Brain Barrier Dysfunction and Integrity by Suppressing Pyroptosis Activation. Front Cell Neurosci. 2021;14:449 [cited 2021 Feb 1] Available from: https://www.frontiersin.org/articles/10.3389/fncel.2020.540669/full.
Article Google Scholar
Nagyoszi P, Nyúl-Tõth Á, Fazakas C, Wilhelm I, Kozma M, Molnár J, et al. Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells. J Neurochem. 2015;135(3):551–64 [cited 2021 Sep 15] Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/jnc.13197.
Article CAS PubMed Google Scholar
Chen Y, Wang L, Pitzer AL, Li X, Li PL, Zhang Y. Contribution of redox-dependent activation of endothelial Nlrp3 inflammasomes to hyperglycemia-induced endothelial dysfunction. J Mol Med. 2016;94(12):1335–47 [cited 2021 Sep 14] Available from: https://pubmed.ncbi.nlm.nih.gov/27783111/.
Article CAS PubMed Google Scholar
Zhang Y, Chen Y, Zhang Y, Li PL, Li X. Contribution of cathepsin B-dependent Nlrp3 inflammasome activation to nicotine-induced endothelial barrier dysfunction. Eur J Pharmacol. 2019;865:172795 [cited 2021 Sep 14] Available from: https://pubmed.ncbi.nlm.nih.gov/31733211/.
Article CAS PubMed PubMed Central Google Scholar
Cao G, Jiang N, Hu Y, Zhang Y, Wang G, Yin M, et al. Ruscogenin attenuates cerebral ischemia-induced blood-brain barrier dysfunction by suppressing TXNIP/NLRP3 inflammasome activation and the MAPK pathway. Int J Mol Sci. 2016;17(9) [cited 2021 Sep 15] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037697/.
Nyúl-Tóth Á, Kozma M, Nagyőszi P, Nagy K, Fazakas C, Haskó J, et al. Expression of pattern recognition receptors and activation of the non-canonical inflammasome pathway in brain pericytes. Brain Behav Immun. 2017;64:220–31.
Article PubMed Google Scholar
Rock KL, Kono H. The inflammatory response to cell death. Vol. 3, Annual Review of Pathology: Mechanisms of Disease. NIH Public Access; 2008 [cited 2021 Jan 4]. p. 99–126. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094097/
Ismael S, Zhao L, Nasoohi S, Ishrat T. Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke. Sci Rep. 2018;8(1):1–9 [cited 2021 Feb 1] Available from: https://www.nature.com/articles/s41598-018-24350-x.
Article CAS Google Scholar
Matsuyama H, Shindo A, Shimada T, Yata K, Wakita H, Takahashi R, et al. Chronic cerebral hypoperfusion activates AIM2 and NLRP3 inflammasome. Brain Res. 2020;1736:146779 [cited 2020 Jun 6] Available from: http://www.ncbi.nlm.nih.gov/pubmed/32171704.
Article CAS PubMed Google Scholar
Lee KM, Bang J, Kim BY, Lee IS, Han J-S, Hwang BY, et al. Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling. BMC Complement Altern Med. 2015;15(1):125 [cited 2021 Mar 11] Available from: http://bmccomplementalternmed.biomedcentral.com/articles/10.1186/s12906-015-0652-1.
Article PubMed PubMed Central Google Scholar
Manso Y, Holland PR, Kitamura A, Szymkowiak S, Duncombe J, Hennessy E, et al. Minocycline reduces microgliosis and improves subcortical white matter function in a model of cerebral vascular disease. Glia. 2018;66(1):34–46.
Article PubMed Google Scholar
Frostegård J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, et al. Cytokine expression in advanced human atherosclerotic plaques: Dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999;145(1):33–43 [cited 2021 Jan 22];145(1):33–43 Available from: https://pubmed.ncbi.nlm.nih.gov/10428293/.
Article PubMed Google Scholar
Paramel Varghese G, Folkersen L, Strawbridge RJ, Halvorsen B, Yndestad A, Ranheim T, et al. NLRP3 Inflammasome Expression and Activation in Human Atherosclerosis. J Am Heart Assoc. 2016;5(5). [cited 2021 Sep 2] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889178/
Dziedzic T, Slowik A, Pera J, Szczudlik A. Interleukin 1 Beta Polymorphism (−511) and Risk of Stroke due to Small Vessel Disease. Cerebrovasc Dis. 2005;20(5):299–303 [cited 2021 Jan 22] Available from: https://www.karger.com/Article/FullText/87928.
Article CAS PubMed Google Scholar
Zhou D, Wang X, Chen T, Wen W, Liu Y, Wu Y, et al. The NLRP3 rs10754558 polymorphism is associated with the occurrence and prognosis of coronary artery disease in the Chinese Han population. Biomed Res Int. 2016 [cited 2021 Sep 11];2016. Available from: https://doi.org/10.1155/2016/3185397.
Hitomi Y, Ebisawa M, Tomikawa M, Imai T, Komata T, Hirota T, et al. Associations of functional NLRP3 polymorphisms with susceptibility to food-induced anaphylaxis and aspirin-induced asthma. J Allergy Clin Immunol. 2009;124(4):779–785.e6 [cited 2021 Sep 11] Available from: http://www.jacionline.org/article/S0091674909011518/fulltext.
Article CAS PubMed Google Scholar
Trøseid M, Seljeflot I, Hjerkinn EM, Arnesen H. Interleukin-18 is a strong predictor of cardiovascular events in elderly men with the metabolic syndrome synergistic effect of inflammation and hyperglycemia. Diabetes Care. 2009;32(3):486–92 [cited 2021 Jan 22] Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646034/.
Article PubMed PubMed Central Google Scholar
Ji Q, Zeng Q, Huang Y, Shi Y, Lin Y, Lu Z, et al. Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome. Mediat Inflamm. 2014;2014.
Chauhan D, Vande Walle L, Lamkanfi M. Therapeutic modulation of inflammasome pathways. Immunol Rev. 2020;297(1):123–38 [cited 2021 Jan 22] Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/imr.12908.
Article CAS PubMed PubMed Central Google Scholar
Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61 [cited 2016 Feb 18] Available from: http://www.annualreviews.org.libproxy1.nus.edu.sg/doi/full/10.1146/annurev-cellbio-101011-155745.
Article CAS PubMed Google Scholar

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Funding

This work was supported by the National Medical Research Council Research Grants (NMRC-CBRG-0102/2016; NMRC/CSA-SI/007/2016 and NMRC/OFIRG/0036/2017), Singapore.

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Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Luting Poh, Wei Liang Sim & David Y. Fann
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
Dong-Gyu Jo & Thiruma V. Arumugam
Centre for Cardiovascular Biology and Disease Research, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC, Australia
Quynh Nhu Dinh, Grant R. Drummond, Christopher G. Sobey & Thiruma V. Arumugam
Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Christopher Li-Hsian Chen & Mitchell K. P. Lai
Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Christopher Li-Hsian Chen
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
David Y. Fann
Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
David Y. Fann
Centre for Healthy Longevity, National University Health System (NUHS), Singapore, Singapore
David Y. Fann

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Luting Poh
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LP, WLS, DYF led the writing of the manuscript and devised all the figures. DGJ, QND, GRD, CGS and MKPL edited the manuscript. TVA and CLHC supervised the writing and co-edited the manuscript. All authors read and approved the final manuscript.

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Poh, L., Sim, W.L., Jo, DG. et al. The role of inflammasomes in vascular cognitive impairment. Mol Neurodegeneration 17, 4 (2022). https://doi.org/10.1186/s13024-021-00506-8

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Received: 12 June 2021
Accepted: 02 December 2021
Published: 09 January 2022
DOI: https://doi.org/10.1186/s13024-021-00506-8

The role of inflammasomes in vascular cognitive impairment

Abstract

Dementia: a focus on vascular cognitive impairment

Chronic Cerebral Hypoperfusion (CCH): a primary driver of VCI

Pathogenic molecular mechanisms of CCH

Bioenergetic impairment and ionic imbalance

Excitotoxicity

Oxidative stress

Neuroinflammation

Pathogenic cellular mechanisms of CCH

Glial activation

Blood-Brain barrier dysfunction and breakdown

Cell death: necrosis and apoptosis

Demyelination

Pathological Structural features and cognitive impairment from CCH

White matter Lesions

Microinfarcts

Hippocampal atrophy

Cognitive dysfunction in VCI

Inflammation – a critical molecular mechanism and a bridge between CCH and various cellular mechanisms

Inflammasome signaling pathway: linking IL-1 to VCI

Overview of the Inflammasome signaling pathway

Molecular structure of Inflammasome components

Possible Inflammasome-inducing stimuli in VCI

Formation of the Inflammasome complex

Impact of the Inflammasome signaling pathway

Proinflammatory effect of IL-1β and IL-18

Effect of Caspase-1, − 8 and − 11 on cell death pathways

Inflammasomes in Glial activation

Inflammasomes in BBB dysfunction

Inflammasome mediated cell death and neuronal loss

Role of Inflammasomes in demyelination and WMLs

Evidence of inflammasome activity in VCI in humans

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Keywords

Molecular Neurodegeneration

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