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

Award Number: R01AG092255
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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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).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $757,261 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	2	6/22/2026	NON-COMPETING CONTINUATION	$757,261
														Subtotal = $757,261

Issue Date FY: 2025 ( Subtotal = $768,131 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Aging Research	000	1	6/27/2025	NEW	$768,131
														Subtotal = $768,131

Grand Total All Awards = $1,525,392

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

Award Number: R01AG092255

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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