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 disease4,5. 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 disease46-49. Our group and another group independently discovered in the central nervous system of PWH reduced levels of TREM232,42, a receptor expressed on the surface of macrophages that when dysfunctional is associated with increased risk for Alzheimer?s disease6-17,33. New preliminary findings show that HIV infection and antiretroviral therapy can alter TREM2 levels in macrophages, suggesting a possible mechanism for reduced TREM2 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 and other neurodegenerative diseases. TREM2 is an immunomodulatory receptor expressed on the surface of microglia and perivascular macrophages in the brain33. Functional TREM2 surveys the brain for extracellular protein aggregates (Ab) and injured cells and modulates inflammation6-17. Loss of function mutations in TREM2 are associated with increased risk for Alzheimer?s disease40,41. Alzheimer?s disease-like pathology, including increased inflammatory cytokine expression and increased Ab, has been reported in postmortem brains of PWH25,27,55. Despite these findings, how TREM2 functions in the brain during HIV-infection in unknown. We have shown that in HAND brains compared to HIV+ cognitive normal, particularly in Hispanics, TREM2 expression is decreased on microglia, while levels of Ab and inflammatory cytokines are increased32. In vitro, HIV infection and inflammatory cytokines reduce TREM2 expression by monocyte-derived macrophages (MDM), suggesting a possible mechanism by which HIV reduces microglial TREM2. Lastly, we discovered reduced TREM2 levels in brains from a transgenic mouse model for HIV-induced neurotoxicity and Alzheimer?s disease, compared to their wild-type littermates. Therefore, we hypothesize that HIV-induced alterations in TREM2 function and expression promote neuroinflammation and neurodegeneration leading to AD-like neuropathogenesis. This hypothesis will be tested within the three following aims:
AIM 1 : Investigate TREM2 pathway expression in a mouse model for Alzheimer?s disease and HIV infection of the brain.
AIM 2 : Elucidate the role of TREM2 in the differentiation of MDMs exposed to HIV, ART, and inflammatory stimuli.
AIM 3 : Investigate expression of TREM2 in brain samples from HIV+ and HIV- aMCI cases and compare to HIV+ and HIV- CN cases.
Aims 2 and 3 will investigate if TREM2 alterations may be more prevalent in Hispanics.

Public Health Relevance

5.7 million Americans are living with Alzheimer?s disease and by the year 2050 this number is projected to rise to 14 million. While the etiology of Alzheimer?s disease is largely unknown, evidence suggest that in some cases viral infection of the brain or other pathogens may induce inflammatory pathways that lead to Alzheimer?s disease neuropathogenesis. These proposed studies will investigate human immunodeficiency virus infection of the brain as a stimulus to promote Alzheimer?s disease neuropathogenesis through dysregulation of inflammatory signaling. !

National Institute of Health (NIH)
National Institute on Aging (NIA)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZRG1)
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Mackiewicz, Miroslaw
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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