Parkinson’s disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases,

Alzheimer’s disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre

Recent genetic studies on Alzheimer’s disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial

To the editor The APOE gene is a known genetic risk factor for neurodegeneration and cardiovascular disease (CVD) [1, 2]. Beyond the known effects of APOE ε2 and APOE ε4, several rare and protective APOE variants (R154S Christchurch (APOECh), V236E Jacksonville, and R251G) have been identified recently [3, 4]. The ultra-rare APOECh mutation (NM_000041.4(APOE):c.460C > A (p.Arg154Ser)), also known as

Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different

Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer’s disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective. Herein, we review some key findings from clinical and animal model investigations, discussing the role of microglial genetics in mediating perturbations from homeostasis. We note that impairment to

Dr. Donald L. Price, one of the most prolific and distinguished neuroscientists in the field of Alzheimer’s disease and neurodegeneration, has passed. Don was a pioneer in clinical and experimental neuropathology, a devoted husband, father and grandfather, and a mentor to a legion of scientists who followed him. Don was a quintessential renaissance man who read literature in college and thereafter

Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function

This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated

Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Blood samples from 693 participants

The study that found phospho-serine129 in the Parkinson’s-linked protein alpha-synuclein over two decades ago proposed a physiological role in regulating protein function, but this notion was neglected when alpha-synuclein serine129 phosphorylation was identified in Lewy bodies/neurites, the hallmark pathology of synucleinopathies. Recent work suggests that both are relevant: pathological phospho-serine129

Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment

The lack of effective therapies that slow the progression of Alzheimer’s disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular

Molecular Neurodegeneration (2023) 18:74 https://doi.org/10.1186/s13024-023-00663-y In the original article [1] the following statement of funding acknowledgement was mistakenly omitted: “Preclinical studies have been supported by NIH grants P01AG017617 and R01AG062376 grants to RAN.” Authors and Affiliations CervoMed Inc, 20 Park Plaza, Suite 424, Boston, MA, 02116, USA John J. Alam Center for Dementia

Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson’s disease

DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through

In their recent article in Nature, Gulen et al. [1] established the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway as a regulatory driver of inflammaging-associated neurodegeneration in mice. Pharmacological blockade of this pathway in aged mice prevented inflammaging and improved cognitive and motor performance. In the same vein, chemical intervention attenuated a toxic

Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox

Microhemorrhages as a consequence of anti-Ab immunotherapy were first identified over 20 years ago in a single page report in Science by Pfeifer et al. [1]. Following on from that, both Wilcock and Racke reported microhemorrhages in 2004 and 2005 respectively, in different animal models and with different Ab antibodies [2, 3]. When vasogenic edema and microhemorrhages were identified in clinical trials

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous

Recent advances in understanding the pathogenic mechanisms underlying basal forebrain cholinergic (BFC) neuronal degeneration and MRI-based studies provide insight on the contribution of such degeneration at various stages of Alzheimer’s disease (AD) and related dementias and have renewed interest in disease-modifying approaches to treat BFC degeneration. Herein we comment on two recent related publications

Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages

Correction: Mol Neurodegeneration 11, 59 (2016) https://doi.org/10.1186/s13024-016-0124-1 Correction The original article [1] contains an error whereby, in the Methods section on page 3, the last sentence on the left column (continuing to the right column) reads: ‘D7-BIN1 reactions used the same exon 5 sense primer and a junctional antisense primer, 5’-GCTTTCTCAAGCAGCGAGAC-3’, corresponding to the

Most Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD

With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states. Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers

Molecular Neurodegeneration (2023) 18:41 https://doi.org/10.1186/s13024-023-00630-7. The original article [1] contained errors in the Funding section. The correct Funding information can be viewed ahead: Funding This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science, ICT and Future Planning (MSIP) (NRF-2020R1A5A1019023 to Y.T.K., NRF-2021R1A2B5B03002614

RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing infcreases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer’s

The optic nerve is an important tissue in glaucoma and the unmyelinated nerve head region remains an important site of many early neurodegenerative changes. In both humans and mice, astrocytes constitute the major glial cell type in the region, and in glaucoma they become reactive, influencing the optic nerve head (ONH) microenvironment and disease outcome. Despite recognizing their importance in the

Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. BAX activation occurs in two stages including translocation of latent BAX to the mitochondrial outer membrane (MOM) and then permeabilization of the MOM to facilitate the release of apoptotic signaling molecules. As a critical component of RGC death, BAX is an attractive target for neuroprotective

Alzheimer’s disease (AD) was described over a century ago as a disease of dementia with the presence of amyloid and tau pathologies [1], but the past year has seen the first clear evidence that effective disease-modifying anti-amyloid antibody (AAA) therapies are possible. Both aducanumab [2] (from Biogen) and lecanemab [3, 4] (from an Eisai-Biogen collaboration) earned accelerated approval from the

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be

The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal

ApoE4, the most significant genetic risk factor for late-onset Alzheimer’s disease (AD), sequesters a pro-synaptogenic Reelin receptor, Apoer2, in the endosomal compartment and prevents its normal recycling. In the adult brain, Reelin potentiates excitatory synapses and thereby protects against amyloid-β toxicity. Recently, a gain-of-function mutation in Reelin that is protective against early-onset

The accumulation of amyloid beta (Aβ) peptides in fibrils is prerequisite for Alzheimer’s disease (AD). Our understanding of the proteins that promote Aβ fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts. To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical

Plasma assays for the detection of Alzheimer’s disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-β burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer 11C-Deuterium-L-Deprenyl (11C-DED)

Amyloid-related imaging abnormalities (ARIA) have been identified as the most common and serious adverse events resulting from pathological changes in the cerebral vasculature during several recent anti-amyloid-β (Aβ) immunotherapy trials. However, the precise cellular and molecular mechanisms underlying how amyloid immunotherapy enhances cerebral amyloid angiopathy (CAA)-mediated alterations in vascular

RNA translation is tightly controlled in eukaryotic cells to regulate gene expression and maintain proteome homeostasis. RNA binding proteins, translation factors, and cell signaling pathways all modulate the translation process. Defective translation is involved in multiple neurological diseases including amyotrophic lateral sclerosis (ALS). ALS is a progressive neurodegenerative disorder and poses

Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction

Age is the strongest risk factor for the development of Alzheimer’s disease (AD). Besides the pathological hallmarks of β-amyloid (Aβ) plaques and neurofibrillary tangles, emerging evidence demonstrates a critical role of microglia and neuroinflammation in AD pathogenesis. Oleoylethanolamide (OEA) is an endogenous lipid amide that has been shown to promote lifespan and healthspan in C. elegans through

Alzheimer’s disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of

Mutations of the gene TMEM106B are risk factors for diverse neurodegenerative diseases. Previous understanding of the underlying mechanism focused on the impairment of lysosome biogenesis caused by TMEM106B loss-of-function. However, mutations in TMEM106B increase its expression level, thus the molecular process linking these mutations to the apparent disruption in TMEM106B function remains mysterious

The prion-like propagation of tau in neurodegenerative disorders implies that misfolded pathological tau can recruit the normal protein and template its aggregation. Here, we report the methods for the development of sensitive biosensor cell lines for the detection of tau seeding activity. We performed the rational design of novel tau probes based on the current structural knowledge of pathological

The AAA+ ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part of a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, and disease conditions. A large number of mutations have revealed the importance of VCP for human health. In particular, VCP facilitates the dismantling of

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene cause late-onset, autosomal dominant Parkinson’s disease (PD), with a single missense mutation (Asp620Asn, D620N) known to segregate with disease in families with PD. The VPS35 gene encodes a core component of the retromer complex, involved in the endosomal sorting and recycling of transmembrane cargo proteins. VPS35-linked PD is clinically

Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding

Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of aging (NDAs), such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Glucose is the major brain fuel and glucose hypometabolism has been observed in brain regions vulnerable to aging and NDAs. Many neurodegenerative susceptible regions

Despite being twice as likely to get Alzheimer’s disease (AD), African Americans have been grossly underrepresented in AD research. While emerging evidence indicates that African Americans with AD have lower cerebrospinal fluid (CSF) levels of Tau compared to Caucasians, other differences in AD CSF biomarkers have not been fully elucidated. Here, we performed unbiased proteomic profiling of CSF from

Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer’s disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood. We

Vascular cognitive impairment and dementia (VCID) is commonly caused by vascular injuries in cerebral large and small vessels and is a key driver of age-related cognitive decline. Severe VCID includes post-stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. While VCID is acknowledged as the second most common form of dementia after Alzheimer’s disease

Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined. To study whether the GMB modulates astrocyte

Braak’s hypothesis states that sporadic Parkinson’s disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could

Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background

Recent advances in Alzheimer disease (AD) therapeutics represent a step in the right direction for patients with AD. In recent phase 3 trials for early symptomatic AD, lecanemab (CLARITY-AD) and donanemab (TRAILBLAZER-ALZ2) led to slowing of cognitive and functional decline, and positive alterations on disease-specific biomarkers [1, 2]. The substantial complexities of these new therapies highlight

There are currently no disease-modifying therapeutics for Parkinson’s disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches to delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further disease progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a therapeutic modality to target α-syn. However

More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function

Alzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate

Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray

Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer’s disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory

Alzheimer’s disease (AD) is the most common cause of dementia and a multifactorial disorder affecting around 50 million people worldwide. It is characterized by progressive cognitive impairment eventually leading to death. Postmortem findings of AD pathological hallmarks remain as the main criteria for a definitive diagnosis, despite considerable advances in diagnostic biomarkers. The identification

Axon degeneration and Neuromuscular Junction (NMJ) disruption are key pathologies in the fatal neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). Despite accumulating evidence that axons and NMJs are impacted at a very early stage of the disease, current knowledge about the mechanisms leading to their degeneration remains elusive. Cytoplasmic mislocalization and accumulation of the protein