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

• 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
• 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' s Disease; Alzheimer' 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; ADORA2A gene; AIDS dementia; Adenosine; Age; Aging; Alzheimer' s Disease; Alzheimer' 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

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.

项目摘要： 乙液流体清除系统促进了间质流体（ISF）和脑脊液的交换 通过动脉周围空间进入大脑。此过程由Aquaporin-4（AQP4）部分编写 水通道主要位于星形胶质细胞端脚上，毗邻血脑屏障的内皮细胞。 AQP4从星形胶质细胞端脚到SOMA的表达水平的变化或错误定位会导致 降低的ISF流量导致堆积细胞外废物，例如高磷酸化tau（PTAU）。 PTAU积累是阿尔茨海默氏病（AD）的神经病理学标志 人类免疫缺陷病毒（HIV）。大约50％的艾滋病毒（PWH）患有艾滋病毒的人 相关的神经认知障碍（手），这是一种与认知和运动有关的频谱疾病 PWH下降。有限的研究表明，在HIV CNS感染中AQP4在大脑中的表达水平 来自PWH的中额回的匀浆，有症状的手显着增加 与无症状的手相比 本地化可能会导致认知状况。另外，在中常见的单核苷酸多态性（SNP） AQP4基因与某些神经退行性疾病的认知能力下降有关。 因此，AQP4中的常见突变，亚细胞错误定位，功能障碍，表达可能 电平或翻译后修改有助于手。其他神经炎性疾病的研究 通过腺苷A2AR（A2AR）信号传导显示AQP4的失调。 A2AR激活导致 PKC介导的AQP4（SER180，SER276）的抑制性磷酸化提议有助于通道 内部化，错误定位和改善的表达。我的总体假设是，在PWH中， AQP4可能部分通过降低有毒异常蛋白和HIV的清除率而促成 机械学上通过A2AR失调的部分来改变AQP4。为了检验这一假设，我们提出了三个 具体目标。 AIM 1：确定AQP4和相关途径是否在PWH和 与CI状态和PTAU和A蓄积相关联。我们假设AQP4水平和本地化 在死亡时CI更严重的HIV患者和PTAU证据中，A2AR信号传导被破坏 积累。 AIM 2：确定AQP4 SNP是否与PWH中CI状态的变化相关联。协会 PLWH中具有不同级别CI的AQP4中的常见SNP。我们假设HIV改变了AQP4功能 以及通过PKC介导的AQP4（SER180，SER276）+/- CART的抑制性磷酸化的定位。目标3： 确定HIV在体外如何改变AQP4在星形胶质细胞中的作用。我们假设HIV改变了AQP4 通过PKC介导的AQP4（SER180，SER276）+/- CART的抑制性磷酸化的功能和定位。 来自这些研究的数据可能导致发现艾滋病毒和抗逆转录病毒疗法的新机制 在衰老PWH中起作用的AQP4受损。