Tat endolysosome escape and HAND

项目摘要 抗逆转录病毒治疗(ART)药物大大延长了HIV-1感染者/艾滋病患者的寿命。 然而，这些人经历了大约50%的HIV-1相关神经认知障碍的患病率 (手)。HIV-1感染者的临床表现和病理特征日益受到关注 阿尔茨海默病(AD)包括认知障碍、淀粉样β蛋白(Aβ)水平升高、 磷酸化tau蛋白(p-tau)水平升高，以及突触功能障碍。不仅是因为其发病机制 目前尚不清楚，但对HIV-1、HIV-1蛋白和/或ART的影响程度知之甚少 药物扮演着“衰老和阿尔茨海默氏症加速器”的角色。这项专注于阿尔茨海默氏症的管理的目标 补充剂(非-AG-20-008)是为了确定HIV-1 Tat蛋白的程度和机制 有助于AD样病理的发展。我们的中心假设是HIV-1TAT与 内酶体中的SLC38A9精氨酸传感器促进v-ATPase质子泵在体内的分解 内溶酶体，并引起AD样病理。在我们初步发现的指导下，这一新的假设将 通过追求两个具体目标来接受考验。(1)确定TAT的程度和机制 导致v-ATPase解体。(2)确定TAT诱导v-的程度和机制。 在原代培养的神经元中，ATPase的分解导致AD样病理。这里提议的研究将 探索TAT通过溶酶体精氨酸传感器诱导v-ATPase分解的新机制， 我们将重点研究TAT诱导的v-ATPase分解如何在AD样发病机制中发挥作用。此外， 我们预计，促进v-ATPase的组装将减轻TAT诱导的AD样病理。这个 建议的研究属于获奖的R01(MH119000-01)的范围，不侧重于AD或其 与痴呆相关，而不是v-ATPase参与TAT内溶酶体逃逸和手部。结果： 拟议的研究不仅将导致对手部和骨骼肌萎缩侧索硬化症共同发病机制的新见解。 AD，但也为开发内溶酶体酸化剂作为新的治疗策略提供了理论基础。

Project Abstract Antiretroviral therapeutic (ART) drugs have greatly increased the lifespan of people living with HIV-1/AIDS. However, these same people experience ~50% prevalence rates of HIV-1 associated neurocognitive disorders (HAND). Increasingly noted in HIV-1 infected individuals are clinical manifestations and pathological features of Alzheimer’s disease (AD) including cognitive impairment, increased levels of amyloid beta protein (Aβ), increased levels of phosphorylated tau protein (p-tau), and synaptic dysfunction. Not only is the pathogenesis of HAND unclear, but relatively little is known about the extent to which HIV-1, HIV-1 proteins, and/or ART drugs act as “aging and AD accelerators”. The objective for this Alzheimer’s-focused Administrative Supplement (NOT-AG-20-008) is to determine the extent to which and mechanisms by which HIV-1 Tat protein contributes to the development of AD-like pathology. Our central hypothesis is that HIV-1 Tat interacts with the SLC38A9 arginine sensor in endolysosomes, promotes the disassembly of the v-ATPase proton pump in endolysosomes, and causes AD-like pathology. Guided by our preliminary findings, this novel hypothesis will be tested by pursuing two specific aims. (1) Determine the extent to which and mechanisms by which Tat causes v-ATPase disassembly. (2) Determine the extent to which and mechanisms by which Tat induced v- ATPase disassembly causes AD-like pathology in primary cultured neurons. The proposed studies here will explore novel mechanisms whereby Tat induces disassembly of v-ATPase via a lysosome arginine sensor, and we will focus on how Tat-induced disassembly of v-ATPase contributes to AD-like pathogenesis. Further, we expect that promoting the assembly of v-ATPase will attenuate Tat-induced AD-like pathology. The proposed studies are within the scope of the awarded R01 (MH119000-01) that is focused not on AD or its related dementias, but rather an involvement of v-ATPase in Tat endolysosome escape and HAND. Results of the proposed studies will not only lead to novel mechanistic insights into the co-pathogenesis of HAND and AD, but also provide rationale for developing endolysosome-acidifying agents as novel therapeutic strategies.