HIV induces AQP4 dysfunction and aberrant waste clearance from brain leading to worsening HAND

HIV 诱导 AQP4 功能障碍和大脑废物清除异常，导致手部疾病恶化

基本信息

批准号：
10619083
负责人：
Dianne Teresa LANGFORD
金额：
$ 43.59万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10619083
关键词：
ADORA2A gene AIDS dementia Adenosine Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Astrocytes Blood Brain Case-Control Studies Cells Central Nervous System Infections Cerebrospinal Fluid Cervical lymph node group Cessation of life Coculture Techniques Cognitive Data Disease Endothelial Cells Exposure to Flushing Frontal gyrus Functional disorder G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs General Population Genes HIV HIV antiretroviral HIV-associated neurocognitive disorder Human Impaired cognition Impairment In Vitro Injury Intercellular Fluid Knowledge Lead Link Liquid substance Mediating Motor Mutation Nerve Degeneration Neurocognitive Deficit Neurodegenerative Disorders Participant Pathway interactions Patients Persons Phosphorylation Physiological Post-Translational Protein Processing Process Proteins Proteome Proteomics Quality of life Receptor Activation Receptor Signaling Reporting Research Design Research Personnel Risk Factors Rodent Sepharose Signal Transduction Single Nucleotide Polymorphism System Testing Traumatic Brain Injury Waste Products age related aging brain antiretroviral therapy aquaporin 4 brain abnormalities brain cell brain endothelial cell brain tissue chronic traumatic encephalopathy cohort extracellular fluid flow foot glymphatic clearance glymphatic dysfunction glymphatic function glymphatic system hyperphosphorylated tau improved macrophage neurocognitive disorder neuroinflammation neuronal cell body normal aging receptor risk variant sex wasting water channel

项目摘要

Project Summary: The 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 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. In addition, common single nucleotide polymorphisms (SNPs) in the aqp4 gene have been associated with more rapid cognitive decline in some neurodegenerative diseases. Therefore, it is possible that common mutations in aqp4, subcellular mislocalization, dysfunction, expression levels or post-translational modifications contribute to HAND. Studies in other neuroinflammatory diseases have shown dysregulation of AQP4 through the adenosine A2aR (A2aR) signaling. A2aR activation leads to PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) that is proposed to contribute to channel internalization, mislocalization and decreased expression. My overall hypothesis is that in PWH, changes in AQP4 may contribute, in part, to HAND by decreasing clearance of toxic aberrant proteins and HIV mechanistically alters AQP4 in part via dysregulation of A2aR. To test this hypothesis, we proposed three specific aims. Aim 1: Determine if AQP4 and associated pathways are altered in brain tissues from PWH and associates with CI status and pTau and Aaccumulation. We hypothesize that AQP4 levels and localization and A2aR signaling are disrupted in HIV patients with more severe CI at death and evidence of pTau accumulation. Aim 2: Determine if aqp4 SNPs are associated with changes in CI status in PWH. Association of common SNPs in aqp4 with different levels of CI in PLWH. We hypothesize that HIV alters AQP4 function and localization via PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) +/- cART. Aim 3: Determine how HIV alters AQP4 functioning in astrocytes in vitro. We hypothesize that HIV alters AQP4 function and localization via PKC-mediated inhibitory phosphorylation of AQP4 (Ser180, Ser276) +/- cART. Data from these studies may lead to the discovery of new mechanisms by which HIV and anti-retroviral therapy contribute to impaired AQP4 functioning in aging PWH.

项目概要：类淋巴液清除系统促进间质液（ISF）和脑脊液的交换水通道蛋白 4 (AQP4) 部分促进了这一过程。水通道主要位于星形胶质细胞末端足部，毗邻血脑屏障的内皮细胞。表达水平的变化或 AQP4 从星形胶质细胞末端脚到体细胞的错误定位可能导致 ISF 流量减少导致细胞外废物（如过度磷酸化 Tau (pTau)）的积聚。 pTau 积累是阿尔茨海默病 (AD) 和某些患有阿尔茨海默病的人的神经病理学标志大约 50% 的艾滋病毒感染者 (PWH) 患有艾滋病毒。相关神经认知障碍 (HAND)，这是一种与认知和运动相关的谱系障碍有限的研究表明，HIV中枢神经系统感染后大脑中AQP4的表达水平下降。患有症状性 HAND 的 PWH 的额中回匀浆显着增加与那些无症状的 HAND 患者相比，这提出了 AQP4 功能和亚细胞是否正常的问题。此外，常见的单核苷酸多态性（SNP）可能有助于认知状态。 aqp4 基因与某些神经退行性疾病中更快的认知能力下降有关。因此，aqp4的常见突变、亚细胞错位、功能障碍、表达可能是水平或翻译后修饰有助于其他神经炎症疾病的 HAND 研究。研究表明，A2aR (A2aR) 信号传导导致 AQP4 失调。 PKC 介导的 AQP4（Ser180、Ser276）抑制性磷酸化被认为有助于通道内化、错误定位和表达减少我的总体假设是，在 PWH 中，变化 AQP4 可能部分通过减少有毒异常蛋白和 HIV 的清除来促进 HAND 为了检验这一假设，我们提出了三个机制，部分是通过 A2aR 的失调来改变 AQP4。具体目标 1：确定 PWH 和脑组织中的 AQP4 和相关通路是否发生改变。与 CI 状态以及 pTau 和 A积累相关。我们勇敢地说 AQP4 水平和本地化。死亡时 CI 更严重且有 pTau 证据的 HIV 患者中，A2aR 和 A2aR 信号传导受到破坏目标 2：确定 aqp4 SNP 是否与 PWH 关联中 CI 状态的变化相关。我们发现艾滋病毒改变了 AQP4 功能。以及通过 PKC 介导的 AQP4（Ser180、Ser276）抑制性磷酸化 +/- cART 进行定位。确定 HIV 如何在体外改变星形胶质细胞中的 AQP4 功能我们发现 HIV 会改变 AQP4。通过 PKC 介导的 AQP4（Ser180、Ser276）+/- cART 抑制性磷酸化实现功能和定位。这些研究的数据可能会发现艾滋病毒和抗逆转录病毒治疗的新机制导致老龄 PWH 中 AQP4 功能受损。