EXPLORING CCR5-MEDIATED HIPPOCAMPAL SYNAPTIC PLASTICITY AND ASSOCIATIVE MEMORY CHANGES IN ALZHEIMER’S DISEASE

Many countries in the world are facing an aging population crisis, with concurrent increased predisposition for neurodegenerative diseases, chiefly Alzheimer’s disease (AD). Though AD is one of the largest causes of dementia-related disorders in the world with massive socioeconomic implications, very few therapeutic solutions exist to counter it. Thus, identifying the underlying processes driving long-term memory impairment in AD could prove beneficial. Synaptic plasticity is the activity-dependent, strengthening or weakening of synaptic connections and is the basis of learning and memory. It is mediated by long-term potentiation (LTP) and synaptic tagging and capture (STC). Impaired synaptic plasticity is a hallmark of AD, and is associated with increased neuroinflammation. Thus, combating neuroinflammation could potentially ameliorate AD-associated memory and cognitive deficits. One promising candidate is CCR5(C–C-chemokine receptor 5) implicated in enhanced inflammatory processes in HIV-associated neurocognitive disorder (HAND), stroke, post-traumatic stress disorder (PTSD), and schizophrenia. Utilizing a combination of field electrophysiology, behavioural tagging studies, and molecular techniques, we have identified that CCR5 overexpression plays a crucial role in mediating AD-associated synaptic impairments, and CCR5 inhibition via its antagonist maraviroc yielded significant improvements in long-term memory and associative plasticity. Our findings also showcase the dynamic effects of CCR5 on structural and functional plasticity mechanisms, providing pivotal evidence of the pathophysiological processes underlying CCR5-mediated AD-memory impairments. Thus, our results identify the significant influence of CCR5 in learning and memory, validating its suitability to be considered as a potential therapeutic option in AD.