Astrocytes at the Crossroads of HIV and Alzheimer’s Disease
Shilpa Buch,
Professor and Senior Executive Vice Chair for Research,
University of Nebraska Medical Center
Increased life expectancy of HIV+ patients in the post anti-retroviral therapy era parallels with increased incidence of HIV-associated neurological disorders (HAND) and associated comorbidities such as Alzheimer’s Disease (AD). The persistence of HAND is thought to involve poor penetration of the antiretroviral drugs across the BBB into the CNS, leading to persistent low-level viral replication in the CNS with accumulation of cytotoxic viral proteins including Tat. Interestingly, there have been reports on Tat-mediated production of the toxic neuronal amyloid protein & the interaction with the former, leading to enhanced toxicity. Additionally, opiates have shown to exaggerate HIV mediated neuropathogenesis in different animal models. Abundant glial cells such as the astrocytes have also garnered interest as potential contributors of amyloidosis, & this could translate into a significant added burden to the process of amyloidosis in the context of Tat & Opiates. Present study was aimed at assessing the role of astrocytes in mediating Tat/Morphine induced amyloidosis in the context of HAND & opiate use disorder. Our in vivo data showed that SIV+ macaques/HIV+ patients, exhibited region specific up-regulation of the amyloidogenic components in the brain that co-localized with GFAP positive astrocytes. In vitro findings aimed at dissecting the cell-type specificity involved in amyloidosis revealed up-regulation of AD markers – BACE-1, amyloid precursor protein (APP), ABetamoC64, p-Tau, as well as increased activity of BACE-1 in Tat-exposed human primary astrocytes (HPA). Molecular mechanism(s) underlying this process involved up-regulation of hypoxia inducible factor (HIF-1a) with a concomitant translocation to the nucleus & binding to the lncRNA BACE-1AS resulting in formation of a unique complex as confirmed by RIP and EMSA. Further, ChiP assay showed functional binding of the complex to BACE-1 promoter leading in turn, to increased expression of BACE-1 by transcriptional, post transcriptional and translational mechanisms along with increased activity leading to consequential generation of ABeta-42 protein via cleavage of APP. We next sought to assess whether morphine-stimulated astrocyte extracellular vesicles (ADEV) could shuttle the amyloid cargoes to neurons. Our results showed that morphine exposure up-regulated the release of morphine-ADEVs, carrying amyloids and that silencing HIF-1Alpha in astrocytes not only reduced the numbers of released ADEVs, but also inhibited the packaging of amyloid cargos in ADEVs. These findings were further validated in brain derived EVs (BEVs) isolated from macaques, wherein it was shown that BEVs from morphine-dependent macaques, carried varieties of amyloid cargoes including the cytokine IL-1Beta. Targeting HIF-1Alpha can thus be considered as an adjunctive therapy approach for HAND patients on cART with a comorbidity of opiate misuse.
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