Review ArticleInsight into the roles of CCR5 in learning and memory in normal and disordered states
Introduction
More than 16 million Americans suffer from cognitive impairments, and that number continues to rise as mean life expectancy increases. Cognitive impairments range from mild to severe and can be the result of natural aging or different psychiatric or neurological disorders. There are few targeted therapies available for these cognitive impairments, partly because cognitive decline can rarely be attributed to a single physiological source; instead, it generally arises from the combinatorial effect of multiple neural dysfunctions. Hence, there is a wide therapeutic gap and a significant need for more exploration into the molecular, cellular and systemic mechanisms underlying cognitive deficits (Bredesen, 2014).
One promising avenue of research is in understanding the relationship between neuroinflammation and cognition. Pro-inflammatory biomarkers have been shown to correlate with the severity of cognitive decline both in the context of age-related impairments and in diseases like Alzheimer’s (Heyser et al., 1997, Lim et al., 2013). Notably, the hippocampus, a brain region critical for learning and memory, has been shown to be particularly susceptible to neural deficits caused by inflammation because of its high expression of inflammatory markers (Lim et al., 2013). These inflammatory markers include IL-1α, IL-1β, IL-6, TNFα, NFκB and chemokine CCL2 (MCP-1) which are involved in microglia activation, synaptic dysfunction, cognitive impairment, AIDS, epilepsy, and impaired adult neurogenesis (da Cunha et al., 2012, Lin et al., 2020, Valcarcel-Ares et al., 2019, Vallières et al., 2002, Vitkovic et al., 2000).
Accumulating evidence indicates that chemokine receptors play an important role in cognition (Stuart and Baune, 2014). One widely studied chemokine receptor is CCR5 (C–C-chemokine receptor 5). CCR5 is a seven-membrane, G protein-coupled receptor (GPCR) highly enriched in the hippocampal CA1 (Torres-Munoz et al., 2004). CCR5 is expressed on a variety of immune cells, including T lymphocytes, macrophages, and dendritic cells. In the brain, it is highly expressed in microglia and to a lesser extent in astrocytes and neurons (Cartier et al., 2005, Fantuzzi et al., 2019, Tran et al., 2007, Westmoreland et al., 2002).
CCR5 has multiple ligands, including CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES). Additional inflammatory chemokines such as CCL8 (MCP-2), CCL3L1 (LD78) and CCL11 (eotaxin) were also found to act as agonists for CCR5 (Bachelerie et al., 2014, Brelot and Chakrabarti, 2018). Through the Gi or Gq subunit of G protein, the binding of chemokine ligands to CCR5 can activate multiple signaling cascades, including phosphoinositide-3 kinase (PI3K), mitogen-activated protein kinases (MAPK) and protein kinase C (PKC) (Brelot and Chakrabarti, 2018, Lorenzen et al., 2018). CCR5 activation also leads to phosphorylation of Janus kinase 2 (JAK2) and the activation of JAK/STAT pathway, which is independent of Gi or Gq activation (Mueller and Strange, 2004). When different chemokines bind to CCR5, the resultant signaling cascades after CCR5 activation lead to calcium flux and chemotaxis of leukocytes, or promote cell survival and cell proliferation. Genetic or pharmacological CCR5 blockade regulates cytokine expression and secretion, including decreased expression of proinflammatory mediators such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and IL-17A, and increased expression of the anti-inflammatory cytokine IL-10, suggesting that CCR5 could serve as an effective therapeutic target for reducing inflammation (Ahmad et al., 2019, Gu et al., 2016, Tang et al., 2015).
Inflammation has been associated with cognitive decline in various neurological or neurodegenerative disorders, including Alzheimer’s disease and HIV-associated cognitive decline (Guha et al., 2019, Paouri and Georgopoulos, 2019, Song et al., 2015). While the studies above have shown a relationship between CCR5 inhibition and decreased inflammation, it must be noted that reduced inflammation is not the only outcome of CCR5 inhibition and therefore not the sole mechanism underlying the effect of CCR5 inhibition on learning and memory and cognitive deficits.
In addition to its role in immune response, CCR5 is predominantly known as a co-receptor for HIV in the central nervous system, and is widely studied in the context of both the viral infection and its related cognitive disorder (Deng et al., 1996, Ellis et al., 2007). In contrast, the role of CCR5 in normal learning and memory, and in memory deficits in mental or neurological disorders, is not well understood. This review will introduce and discuss the current evidence implicating CCR5 in both normal and disordered learning and memory states to pave the path for future research.
Section snippets
CCR5 in normal learning and memory
Several studies have explored the role of CCR5 in normal learning and memory (Table 1), where it has been shown to function as a potent suppressor for hippocampal and cortical neuronal plasticity, and as a consequence, for learning and memory (Zhou et al., 2016) (Fig. 1). Recent evidence suggests that CCR5 may impact learning and memory by acting on CREB signaling, a pathway critical for learning and memory (Josselyn et al., 2004, Sano et al., 2014, Zhou et al., 2009). For example, in a tone
CCR5 and HIV-associated neurocognitive disorder (HAND)
The relationship between CCR5 and HIV is well-studied. CCR5 is the coreceptor used by HIV for entry into the host cell following binding of the viral envelope glycoprotein gp120 to the CD4 receptor. However, less understood is how CCR5 contributes to HIV-associated cognitive deficits, which affect about 50 percent of all HIV-infected individuals, even those undergoing antiretroviral therapy (Clifford and Ances, 2013, Deng et al., 1996, Ru and Tang, 2017). Despite these knowledge gaps, there is
Conclusion
A growing body of evidence points towards chemokine receptors as playing important roles in mediating various types of cognition including learning and memory. CCR5 has been well-studied in the scope of immune response and HIV infection (Ellis et al., 2007, Zhou and Saksena, 2013). However, its role in the context of normal and disorder-associated cognition, is less understood. The existing literature points to a general role of CCR5 in limiting cognitive capabilities in both normal learning
Acknowledgments
We thank Dr. Alcino J. Silva for the discussion of the role of CCR5 in learning and memory and in cognitive deficits associated with different disorders.
References (96)
- et al.
DAPTA, a C-C chemokine receptor 5 (CCR5) antagonist attenuates immune aberrations by downregulating Th9/Th17 immune responses in BTBR T(+) Itpr3tf/J mice
Eur. J. Pharmacol.
(2019) - et al.
CCR5 Revisited: How Mechanisms of HIV Entry Govern AIDS Pathogenesis
J. Mol. Biol.
(2018) - et al.
Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse
Behav. Brain Res.
(2012) - et al.
Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases
Brain Res. Brain Res. Rev.
(2005) - et al.
HIV-associated neurocognitive disorder
Lancet Infect. Dis.
(2013) - et al.
The chemokine receptor CCR5-Delta32 gene mutation is not protective against Alzheimer's disease
Neurosci. Lett.
(2004) - et al.
Astrocytes: Orchestrating synaptic plasticity?
Neuroscience
(2016) - et al.
CCR5 mediates HIV-1 Tat-induced neuroinflammation and influences morphine tolerance, dependence, and reward
Brain Behav. Immun.
(2018) - et al.
New insights on the role of microglia in synaptic pruning in health and disease
Curr. Opin. Neurobiol.
(2016) - et al.
Chemokines (RANTES and MCP-1) and chemokine-receptors (CCR2 and CCR5) gene polymorphisms in Alzheimer's and Parkinson's disease
Neurosci. Lett.
(2004)
Inducible repression of CREB function disrupts amygdala-dependent memory
Neurobiol. Learn. Mem.
The CC chemokine receptor 5 regulates olfactory and social recognition in mice
Neuroscience
A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates
J. Neuroinflam.
CCR5 deficiency induces astrocyte activation, Abeta deposit and impaired memory function
Neurobiol. Learn. Mem.
CCL3, acting via the chemokine receptor CCR5, leads to independent activation of Janus kinase 2 (JAK2) and Gi proteins
FEBS Lett.
Loss of CCR2 expressing non-classical monocytes are associated with cognitive impairment in antiretroviral therapy-naïve HIV-infected Thais
J. Neuroimmunol.
Serum concentrations of chemokines (CCL-5 and CXCL-12), chemokine receptors (CCR-5 and CXCR-4), and IL-6 in patients with posttraumatic stress disorder and avoidant personality disorder
Pharmacol. Rep.
Role of the macrophage inflammatory protein-1alpha/CC chemokine receptor 5 signaling pathway in the neuroinflammatory response and cognitive deficits induced by beta-amyloid peptide
Am. J. Pathol.
Chemokine receptor 5 antagonist D-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease
Neuroscience
CREB regulates memory allocation in the insular cortex
Curr. Biol.
Activation of the chemotactic peptide receptor FPRL1 in monocytes phosphorylates the chemokine receptor CCR5 and attenuates cell responses to selected chemokines
Biochem. Biophys. Res. Commun.
Degenerating synaptic boutons in prion disease: microglia activation without synaptic stripping
Am. J. Pathol.
Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: a systematic review of biomarker studies
Neurosci. Biobehav. Rev.
Gene expression profiles in microdissected neurons from human hippocampal subregions
Brain Res. Mol. Br Res.
Determinants of CCL5-driven mononuclear cell migration across the blood-brain barrier. Implications for therapeutically modulating neuroinflammation
J. Neuroimmunol.
Gene expression profiling of amyloid beta peptide-stimulated human post-mortem brain microglia
Neurobiol. Aging
Developmental expression patterns of CCR5 and CXCR4 in the rhesus macaque brain
J. Neuroimmunol.
Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains
Am. J. Pathol.
Human immunodeficiency virus type 1 protein gp120 causes neuronal cell death in the rat brain by activating caspases
Neurotox. Res.
Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage
Neuropathol. Appl. Neurobiol.
Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions
J. Neuropathol. Exp. Neurol.
International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors
Pharmacol. Rev.
Association between the polymorphism of CCR5 and Alzheimer's disease: results of a study performed on male and female patients from Northern Italy
Ann. N. Y. Acad. Sci.
CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study
J. Neuro. Virol.
Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat
J. Comp. Physiol. Psychol.
Reversal of cognitive decline: a novel therapeutic program
Aging (Albany NY)
Chronic hyperhomocysteinemia increases inflammatory markers in hippocampus and serum of rats
Neurochem. Res.
Identification of a major co-receptor for primary isolates of HIV-1
Nature
Microglial activation - tuning and pruning adult neurogenesis
Front Pharmacol.
HIV and antiretroviral therapy in the brain: neuronal injury and repair
Nat. Rev. Neurosci.
Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders
Cell Mol. Life Sci.
Hotspots of dendritic spine turnover facilitate clustered spine addition and learning and memory
Nat. Commun.
Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder
Aids
Curcumin, the active constituent of turmeric, inhibits amyloid peptide-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating early growth response-1 transcription factor
J. Neurochem.
Mechanism of amyloid peptide induced CCR5 expression in monocytes and its inhibition by siRNA for Egr-1
Am. J. Physiol. Cell Physiol.
Enhanced Chemokine Receptor Expression on Leukocytes of Patients with Alzheimer's Disease
PLoS ONE
Behavioral analysis of CREB alphadelta mutation on a B6/129 F1 hybrid background
Hippocampus
Cited by (24)
CCR5 regulates Aβ<inf>1-42</inf>-induced learning and memory deficits in mice
2024, Neurobiology of Learning and Memory5-HT<inf>7</inf>R enhances neuroimmune resilience and alleviates meningitis by promoting CCR5 ubiquitination
2024, Journal of Advanced ResearchThe role of CCR5 in HIV-associated neurocognitive disorders
2022, HeliyonCitation Excerpt :It must be noted that in early HIV studies, the interaction of gp120 and CCR5 might cause cognitive impairments by causing neuronal apoptosis (Mocchetti et al., 2013; Saylor et al., 2016). With cART, neuronal loss may no longer be the main contributor to HAND (Kelschenbach et al., 2019; Necula et al., 2021). Instead, neuronal dysfunction and synaptodendritic injury after microglia activation may be a more plausible source of cognitive impairment (Ellis et al., 2007; Kelschenbach et al., 2019).
CCR5 deficiency: Decreased neuronal resilience to oxidative stress and increased risk of vascular dementia
2024, Alzheimer's and Dementia
- 1
These authors contributed equally.