The role of TREM2 in Alzheimer's disease related neuropathogenesis in people with HIV

Summary/Abstract This R01 application is for a 5-year project to investigate the role of triggering receptor expressed on myeloid cells (TREM) 2 in Alzheimer's disease pathogenesis in people with HIV (PWH). Alzheimer's disease is the leading cause of dementia in the USA, yet despite many efforts, the cause remains unknown. Some evidence suggests that viral infections can trigger neuropathogenic cascades that lead to Alzheimer's disease. Consistent with this hypothesis, HIV infection is associated with premature aging and may increase the risk for age related neurodegenerative diseases such as Alzheimer's disease and amnestic minor cognitive impairment (aMCI). Our group and another group independently discovered reduced levels of TREM2 in the central nervous system of PWH. This was as significant discovery because TREM2 is an immunomodulatory receptor expressed by brain macrophages: microglia, perivascular macrophages, and infiltrating monocyte derived macrophages. Functional TREM2 surveys the brain for extracellular protein aggregates (Ab) and injured cells and modulates inflammation. Loss of function mutations in TREM2 are associated with increased risk for Alzheimer's disease. Alzheimer's disease-like pathology, including increased inflammatory cytokine expression and increased Ab, has been reported in postmortem brains of PWH. Despite these findings, how TREM2 functions in the brain during HIV-infection is unknown. Our new preliminary findings show that HIV infection and related inflammatory stimuli can alter TREM2 levels in macrophages. This mechanism for reduced TREM2 function may explain the published reports of increased levels of Ab and increased levels of inflammatory cytokines in postmortem brain tissues from PWH with neurocognitive impairment (NCI) compared to neurocognitively unimpaired (NUI) PWH. We also found that cannabinoids at appropriate doses can enhance TREM2 pathway expression and function in macrophages, which could explain why cannabis shows neuroprotective and anti-inflammatory effects in PWH. Understanding how HIV infection may lead to TREM2 dysfunction and Alzheimer's disease-like neuropathogenesis may provide clues to develop therapeutics for these neurodegenerative diseases. Therefore, we hypothesize that HIV modulates TREM2 signaling pathways in a manner that exacerbates neurodegeneration and inflammation, thereby accelerating Alzheimer's disease-like pathogenesis in PWH. This project aims to delineate the specific mechanisms by which HIV alters TREM2 function, exploring innovative pathways that may reveal novel therapeutic targets. This hypothesis will be tested in mice that model the intersection of aging, HIV, and AD neuropathogenesis (Aim 1), in cell culture models for brain macrophages after exposure to HIV, ART, and inflammatory stimuli (Aim 2), and in post-mortem brain tissues from PWH and people without HIV (PWoH), both with and without NCI and aMCI (Aim 3).