Mg-based therapy for mitigating HAND and neuropsychiatric symptoms in the condition of chronic HIV infection

Abstract Microglia (Mg), the brain residential macrophage, play critical roles in maintaining adult brain homeostasis. Mg can function as multi-players such as housekeepers, guards, and warriors under both physiological and pathological conditions. Accumulating evidence reveal that Mg also play vital roles in brain aging. Reversing or

eliminating senescent Mg and replenishing with new-born Mg have been suggested as treatment for aging and neurodegenerative disease. Recently, Mg depletion and repopulation (MgDR) has been tested as a potential therapeutic approach for acute brain injury and Alzheimer’s diseases. Mechanically, the repopulated Mg show

homeostatic phenotype with restoring BDNF signaling or increasing the activity of IL6 pathway to improve brain functions. It has been well-accepted that sustained and lower levels of Mg activation promote Mg senescence and contribute to HAND pathogenesis. Several anti-neuroinflammatory drugs have been proposed as alternative

approach for HAND therapy. However, whether MgDR could be a novel therapeutic approach to mitigate neurological deficiency in chronic HIV (+) individuals have never been explored. We initiated pilot studies and obtained these preliminary data: (1) Both HIV transgenic (Tg) rats and HIV-inducible (i) mice show increased

LDAM in the brains compared to age-matched counterparts; (2) HIV-iTAT mice show dysregulated lipid profile in the brain hippocampus; (3) MgDR by PLX3397 restored locomotion coordination ability in HIV-iTAT male mice. Based on these observations, we hypothesize that LDAM contribute to the pathogenesis of HAND and

neuropsychiatric symptoms and MgDR can exert therapeutic effects on brain dysfunctions in the context of chronic HIV infection. The hypothesis will be tested in the following two specific aims (SA): SA1: Investigate the effects of MgDR on HAND and neuropsychiatric symptoms in HIV-Tg26 mice. SA2: Explore the detailed

mechanisms underlying the effects of MgDR on brain pathology in vivo. This proposal will explore the therapeutic effects of MgDR on brain pathology in the context of chronic HIV infection. If succeed, we could open a new research direction to identify effective therapy to improve the life-quality of chronic HIV (+) individuals.