Alzheimer’s Disease (AD) is the most common cause of neurodegenerative dementia. The major histopathological characters of AD include neuroinflammation, extracellular aggregates of amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The exact mechanisms underlying AD pathology are still not fully understood and remain a subject of intense debates. One of the predominant hypotheses for AD is the amyloid-cascade hypothesis which postulates that the accumulation of amyloid beta peptide in the brain is critical for AD pathogenesis. There are two main types of Aβ peptides, Aβ1-40 and Aβ1-42, which have been found to have a direct relationship to plaque formation and induction of neurotoxicity. Aβ1-40 is relatively more abundant and less neurotoxic compared to Aβ1-42. Conversely, the less abundant Aβ1-42 is highly soluble, neurotoxic and prone to aggregate into toxic Aβ oligomers (Tiwari, Atluri, Kaushik, Yndart, and Nair, 2019). Soluble Aβ peptides have also been reported to regulate the cleavage and phosphorylation of tau protein leading to NFT generation (Lee, Goedert, and Trojanowski, 2001). Aggregation of Aβ1-42 peptides disrupts brain homeostasis and results in neuroinflammation, which accelerates brain deterioration and further contributes to neuronal cell death.

CCR5 is a G-protein coupled receptor (GPCR) and belongs to the β chemokine receptor family. CCR5 is involved in many signaling pathways regulating chemotaxis and cell activation via interactions with its ligands, such as MIP-1ɑ (CCL3), MIP-1β (CCL4), RANTES (CCL5), and other inflammatory chemokines, which can also act as agonists of CCR5 (Alexander, Christopoulos, Davenport, Kelly, Mathie, Peters, Veale, Armstrong, Faccenda, Harding, Pawson, Sharman, Southan, and Davies, 2019). CCR5 activation causes calcium channels to open and promotes cell survival, proliferation and chemotaxis to leukocytes. CCR5 is expressed in macrophages, T-lymphocytes, and dendritic cells in the peripheral system. In the central nervous system (CNS) and under normal conditions, CCR5 is mainly expressed in microglia, specifically in the CA1 region of the hippocampus, which is crucial for learning and memory (Rajagopal, Bassoni, Campbell, Gerard, Gerard, and Wehrman, 2013). However, approximately 12∼24 hours after learning, or under pathological conditions, such as stroke, there is a dramatic increase in neuronal CCR5 expression in the hippocampus and cortex (Joy et al., 2019, Shen et al., 2022), indicating an important role of neuronal CCR5 in the regulation of cognition.

Although the role of CCR5 in HIV infection and HIV-associated neurocognitive disorders (HAND) has been extensively studied, the contribution of CCR5 in learning and memory deficits, especially in neurological or mental disorders, is much less understood (Galimberti et al., 2004, Necula et al., 2021). Brain inflammation is associated with impaired learning and memory in many mental and neurological disorders. Pharmaceutically inhibiting CCR5 not only reduces the expression and secretion of proinflammatory cytokines and chemokines, such as tumor necrosis factor ɑ (TNF-ɑ), interleukin 1β (IL-1β), IL-6 and IL-17A, but also increases the expression of anti-inflammatory cytokine, IL-10 (Ansari et al., 2021, Chen et al., 2022). Besides its role in neuroinflammation, our recent studies found that neuronal CCR5 acts as a potent suppressor of learning and memory (Shen et al., 2022, Zhou et al., 2016). Multiple studies have reported beneficial effects of inhibiting CCR5 on learning and memory, such as enhanced synaptic transmission and plasticity in stroke, traumatic brain injury (TBI), and HAND (Barber, Imaz, Boffito, Niubó, Pozniak, Fortuny, Alonso, Davies, Mandalia, Podzamczer, and Gazzard, 2018; DʼAntoni, Paul, Mitchell, Kohorn, Fischer, Lefebvre, Seyedkazemi, Nakamoto, Walker, Kallianpur, Ogata-Arakaki, Ndhlovu, and Shikuma, 2018; Joy et al., 2019). Altogether, these findings indicate that CCR5 inhibitors may represent a potential treatment for cognitive deficits caused by neuroinflammation in various neurological disorders, including neurodegenerative diseases such as AD.

Li et al. found that Aβ increased CCR5 expression through the transcriptional factor Egr-1, as Aβ enhanced the binding of Egr-1 to the CCR5 promoter, resulting in increased expression of CCR5 (Li, Shang, Zhao, Tian, Li, Fang, Zhu, Man, and Chen, 2009). In addition, expression of the CCR5 receptor ligands, CCL3 and CCL4, was upregulated in microglia in both APP/PS1 mice and post-mortem AD brain (Jorda et al., 2019, Walker et al., 2001), suggesting a close correlation between CCR5 expression or activation and AD. Currently, most studies have concluded that CCR5 overactivation exacerbates the development of AD (Passos, Figueiredo, Prediger, Pandolfo, Duarte, Medeiros, and Calixto, 2009). However, some studies found that there was no significant association between the CCR5Δ32 polymorphism and AD (Combarros et al., 2004, Wojta et al., 2020), possibly due to the lack of homozygous CCR5Δ32 subjects in these studies.

The present study was designed to further clarify the roles of CCR5 in AD. Our study demonstrated that direct injection of Aβ1-42 peptide in the dorsal CA1 region of the hippocampus resulted in learning and memory impairment. Aβ1-42 injection also caused a long-lasting increase in Ccr5, Ccl3, and Ccl4 in the dorsal hippocampus. Injection of AAV containing shRNA-CCR5-GFP significantly reduced Ccr5 expression in the dorsal hippocampus and rescued the memory impairments induced by Aβ1-42, possibly by interfering with Aβ1-42-induced microglia activation in dorsal CA1 but not in dentate gyrus (DG). The results showed that CCR5 plays an important role in modulating learning and memory in AD. CCR5 antagonists such as maraviroc may serve as potential treatments to improve learning and memory deficits associated with AD.