Abstract

HIV and Opioid-Mediated Aging and Cognitive Decline: Implications for Astrocyte EVs

Shilpa Buch, Professor and Senior Executive Vice Chair for Research, University of Nebraska Medical Center

Although cART usage has increased the lifespan of HIV+ individuals, paradoxically, its dependence is also associated with increased risk of comorbidity of HIV-Associated Neurocognitive Disorders (HAND). Heroin abuse can accelerate the process of HAND pathogenesis, specifically age-sensitive brain functional networks in patients. Based on our previous findings that astrocytes play a major role in HIV Tat & Morphine-mediated amyloidosis & senescence-like phenotype, and since these senescence associated secretory phenotype (SASP) cargoes can be released in extracellular vesicles (EVs), we sought to assess whether HIV Tat protein and morphine-stimulated astrocyte derived EVs (ADEVs) containing these toxic cargoes could induce synaptodegeneration in neurons invitro and when administered in the brains of naïve mice. This study aims to focus on the cellular cross-talk mediated by ADEVs in inducing synaptodendritic injury. Methods: We assessed the novel role of long noncoding (lnc) RNA BACE1 antisense (AS) in HIV-Tat/morphine mediated astrocytic senescence and amyloidosis and in mediating neuronal injury. Additionally, we assessed the behavioral deficits as well as ageing phenotype in morphine dependent, as well as Tat-ADEV injected mice. Results: Both HIV-Tat and Morphine-induced senescence phenotype (p16, p21, ROS, cell cycle arrest, ß- gal activity, cytokines) and accumulation of amyloids in human astrocytes in culture. Furthermore, using gene silencing approach, we showed that this phenomenon was regulated by lncRNA BACE1AS. Next, EVs isolated from HIV-Tat or morphine exposed human astrocytes were demonstrated to shuttle the SASP cargoes and also that, the EV numbers were regulated by lncRNA BACE1AS. These EVs upon being uptaken by the neurons both in vitro and in vivo, were shown to induce neuronal senescence & synaptodendritic injury. Interestingly, validation in vivo demonstrated that morphine administered mice exhibited ageing phenotype in the frontal cortex and hippocampus and this was associated with cognitive decline. There was also synaptodegeneration in the hippocampi of mice injected with  these ADEVs. Conclusion(s): This study underscores the role of lncRNA BACE1AS in astrocytic senescence and amyloidosis and the role of ADEVs in mediating synaptodegeneration leading to cognitive impairments associated with HAND.