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

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： 胶质淋巴液清除系统促进间质液（ISF）和脑脊液的交换 通过动脉血管周围间隙进入大脑水通道蛋白4（AQP 4）促进了这一过程。 水通道主要位于邻接血脑屏障内皮细胞的星形胶质细胞末端足上。 AQP 4表达水平的变化或从星形胶质细胞终足到索马体的定位错误可导致 减少的ISF流动导致细胞外废物产物如过度磷酸化的Tau（pTau）的积累。 pTau积累是阿尔茨海默病（AD）中的神经病理学标志，并且在一些患有阿尔茨海默病（AD）的人中， 人类免疫缺陷病毒（艾滋病毒）。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， PWH下降。有限的研究表明，在HIV CNS感染中，脑中AQP 4的表达水平 有症状性HAND的PWH患者额中回的匀浆显著增加， 与无症状HAND患者相比，这提出了一个问题，即AQP 4功能和亚细胞 定位可能有助于认知状态。此外，常见的单核苷酸多态性（SNP）， AQP 4基因与某些神经变性疾病中更快速认知下降有关。 因此，aqp 4的常见突变、亚细胞错误定位、功能障碍、表达异常可能是aqp 4基因突变的原因之一。 水平或翻译后修饰有助于HAND。其他神经炎性疾病研究 已经显示出通过腺苷A2 aR（A2 aR）信号传导的AQP 4失调。A2 aR激活导致 PKC介导的AQP 4（Ser 180，Ser 276）的抑制性磷酸化被认为有助于通道 内化、错误定位和表达降低。我的总体假设是，在PWH中， AQP 4可能通过减少毒性异常蛋白和HIV的清除而部分促成HAND。 通过A2 aR的失调部分地机械地改变AQP 4。为了检验这个假设，我们提出了三个 具体目标。目的1：确定是否AQP 4和相关途径在PWH脑组织中发生改变， 与CI状态以及pTau和A β积累相关。我们假设AQP 4水平和定位 和A2 aR信号传导在死亡时具有更严重CI的HIV患者中被破坏，并且有证据表明pTau 积累目的2：确定aqp 4 SNP是否与PWH中CI状态的变化相关。协会 aqp 4中常见的SNPs与PLWH中不同水平的CI之间的关系。我们假设HIV改变了AQP 4的功能， 以及通过PKC介导的AQP 4（Ser 180，Ser 276）+/- cART的抑制性磷酸化的定位。目标三： 确定HIV如何改变AQP 4在体外星形胶质细胞中的功能。我们假设HIV改变了AQP 4 通过PKC介导的AQP 4（Ser 180，Ser 276）+/- cART抑制性磷酸化的功能和定位。 这些研究的数据可能会导致发现艾滋病毒和抗逆转录病毒治疗的新机制。 导致老化PWH中AQP 4功能受损。