Elsevier

Brain, Behavior, and Immunity

Volume 92, February 2021, Pages 1-9
Brain, Behavior, and Immunity

Review Article
Insight into the roles of CCR5 in learning and memory in normal and disordered states

https://doi.org/10.1016/j.bbi.2020.11.037Get rights and content

Highlights

Abstract

As cognitive impairments continue to rise in prevalence, there is an urgent need to understand the mechanisms of learning and memory in normal and disordered states. C–C chemokine receptor 5 (CCR5) has been implicated in the regulation of multiple forms of learning and memory via its regulation on learning-related cell signaling and neuronal plasticity. As a chemokine receptor and a co-receptor for HIV, CCR5′s role in immune response and HIV-associated neurocognitive disorder (HAND) has been widely studied. In contrast, CCR5 is less understood in cognitive deficits associated with other disorders, including Alzheimer’s disease (AD), stroke and certain psychiatric disorders. A broad overview of the present literature shows that CCR5 acts as a potent suppressor of synaptic plasticity and learning and memory, although a few studies have reported the opposite effect of CCR5 in stroke or AD animal models. By summarizing the current literature of CCR5 in animal and human studies of cognition, this review aims to provide a comprehensive overview of the role of CCR5 in learning and memory in both normal and disordered states and to discuss the possibility of CCR5 suppression as an effective therapeutic to alleviate cognitive deficits in HAND, AD, and stroke.

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.

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