Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome

University Of Nebraska Medical Center, Omaha NE

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Abstract

Summary: The parent grant (DA050545) focuses on assessing the role of microglial inflammasome NLRP3 in the context of neuroinflammation mediated by HIV and cocaine use. Since people living with HIV (PLWH) are now enjoying longer life-span, owing to effective combinatorial antiretrovirals, it is no surprise that there is an emerging surge of age-related comorbidities intersecting with the already existent HAND symptomatology in these individuals. In light of this, clinicians are seeing a rise in premature aging and Alzheimer’s-like phenotype in PLWH. Interestingly, in keeping with the clinical findings, studies from our lab have also demonstrated the accumulation of toxic amyloid deposits in the sections of brains from SIV-infected macaques as well as those from HAND patients with cocaine exposure (from NNTC) and, in the brains of HIV Transgenic rats exposed to cocaine (preliminary studies). Furthermore, in our recently reported cell culture study, we have also demonstrated that activated NLRP3 inflammasome generated from HIV Tat-activated microglia can shuttle to the bystander neurons via the extracellular vesicles (EVs), and unpublished data showed these EVs lead to upregulated expression of toxic amyloid proteins in the neurons. Taken together, we thus hypothesize that HIV Tat and cocaine-mediated activation of microglial NLRP3 (parent grant) could be shuttled through the microglial EVs to the recipient neurons to induce toxic amyloids and senescence mediators, which, in turn, could be detected as biomarkers in neuronal enriched EVs isolated from the plasma. While the focus of the parent grant is on understanding the role of activated NLRP3 inflammasome in the context of HIV Tat, and cocaine, the supplement aims to extend these studies to already available, archived plasma and brain samples from groups of SIV-infected rhesus macaques administered with/without cocaine for assessing the amyloid pathology and senescence phenotype in the brains of these animals and brain-derived neuronal EVs in the plasma. We will also correlate the expression of microglial NLRP3 in the brain with NLRP3 in plasma-enriched microglial EVs and expression levels of aging/AD cargos in the plasma-enriched neuronal EVs.