HIV PROMOTES ADENOSINE A2A RECEPTOR MEDIATED AQUAPORIN-4 DYSREGULATION IN ASTROCYTES WHICH MAY CONTRIBUTE TO ACCUMULATION OF ABERRANT PROTEINS IN THE BRAIN

Abstract

The glial-lymphatic or glymphatic fluid clearance system promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid through the arterial perivascular spaces into the brain. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocyte end feet abutting endothelial cells of the blood brain barrier. Changes in expression levels or mislocalization of AQP4 from astrocytic end feet to the soma can lead to decreased ISF flow leading to buildup of extracellular waste products like hyperphosphorylated Tau (pTau). pTau accumulation is a neuropathological hallmark in Alzheimer’s disease (AD) and in some people with human immunodeficiency virus (HIV). Approximately 50% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), which is a spectrum disorder linked to cognitive and motor decline in PWH. Limited studies have shown that in HIV CNS infection that expression levels of AQP4 in brain homogenates from the mid-frontal gyrus of PWH with symptomatic HAND were significantly increased compared to those with asymptomatic HAND, which raises the question if AQP4 function and subcellular localization may contribute to cognitive status. Studies in other neuroinflammatory diseases have shown dysregulation of AQP4 through the adenosine A2aR (A2aR) signaling. A2aR activation leads to PKA/PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) that is proposed to contribute to channel internalization, mislocalization and decreased expression. In addition, common single nucleotide polymorphisms in aqp4 have been associated with more rapid cognitive decline some neurodegenerative diseases. Therefore, it is possible that common mutations in aqp4, subcellular mislocalization, dysfunction, expression levels or post-translational modifications contribute to HAND. Therefore, the cognitive changes we see in HAND maybe due to changes in AQP4 may contribute by decreasing clearance of toxic aberrant proteins and HIV mechanistically alters AQP4 in part via dysregulation of A2aR.