Neuronal endolysosome involvement in HIV-1 Tat-induced amyloid beta accumulation

描述（由申请人提供）： 我们对HIV-1如何与阿尔茨海默病（AD）的发病机制相互作用的理解存在根本性的差距，并确定其潜在机制是我们的长期目标。这项研究的目的是确定转录反式激活因子（达特）的分子机制，这种HIV-1病毒蛋白继续参与HIV-1的免疫应答。 HIV-1相关的神经认知障碍（HAND）的发病机制，最近被牵连在AD样病理的发展，增加神经元A？一代我们的中心假设是，达特增加神经元内A？通过促进APP内化和升高内溶酶体pH值的生产。我们的初步研究结果的指导下，这种新的，未经检验的假设将进行测试，追求两个具体的目标：（1）确定机制，使达特促进APP内化，从而提高APP加工有利于A？生产(2)确定达特升高内溶酶体pH值的机制，从而增强BACE-1活性，有利于A？生产目标#1中提出的工作结果预期将证明LRP-1负责HIV-1蛋白诱导的APP内化增加，并且LRP-1的siRNA敲低阻止HIV-1蛋白诱导的神经元内A？生产目标#2的结果预期证明质子依赖性肽转运蛋白Pept 2负责Tat诱导的内溶酶体pH升高，并且Pept 2的siRNA敲低防止Tat诱导的内溶酶体pH升高、BACE-1的内溶酶体积累增加、BACE-1活性增强和神经元内A？生产这些结果有望为HAND和AD的预防和治疗干预提供新的靶点和理论基础。因此，拟议研究的结果可能在经济、社会和临床上产生重大影响。 公共卫生相关性： 拟议的研究与公共卫生有关，因为HIV-1感染者的长期生存伴随着HIV-1相关神经认知障碍（HAND）的高患病率和阿尔茨海默病（AD）样病理的发病率增加。拟议的研究重点是确定HIV-1病毒蛋白与阿尔茨海默病发病机制相互作用的分子机制。预计这些结果将为我们提供新的目标和理由，用于预防和治疗HAND和AD，因此拟议研究的结果可能在经济，社会和临床上产生重大影响。

DESCRIPTION (provided by applicant): Fundamental gaps exist in our understanding of how HIV-1 may interact with the pathogenesis of Alzheimer's disease (AD), and determining its underlying mechanisms is set as our long-term goal. The objective of the proposed studies is to determine molecular mechanisms whereby transactivator of transcription (Tat), a HIV-1 viral protein that continues to be implicated in the pathogenesis of HIV-1 associated neurocognitive disorder (HAND) and has recently been implicated in the development of AD-like pathology, increases neuronal A? generation. Our central hypothesis is that Tat increases intraneuronal A? production by promoting APP internalization and elevating endolysosome pH. Guided by our preliminary findings, this novel, untested hypothesis will be tested by pursuing two specific aims: (1) Determine mechanisms whereby Tat promotes APP internalization, thus enhancing APP processing in favor of A? production. (2) Determine mechanisms whereby Tat elevates endolysosome pH, thus enhancing BACE-1 activity in favor of A? production. Results from work proposed in Aim #1 are expected to demonstrate that LRP-1 is responsible for HIV-1 protein- induced increases in APP internalization, and that siRNA knockdown of LRP-1 prevents HIV-1 protein-induced intraneuronal A? production. Results from Aim #2 are expected to demonstrate that a proton-dependent peptide transporter, Pept2, is responsible for Tat-induced elevation of endolysosome pH, and that siRNA knockdown of Pept2 prevents Tat-induced elevation of endolysosome pH, increased endolysosome accumulation of BACE-1, enhanced BACE-1 activity, and increased intraneuronal A? production. Such results are expected to provide us with new targets and rationale for preventative and therapeutic interventions against HAND and AD. Thus, the outcome of the proposed studies could have a substantial impact economically, socially and clinically. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health, because the long-term survival of HIV-1 infected individuals is accompanied by a high prevalence of HIV-1 associated neurocognitive disorder (HAND) and an increased incidence of developing Alzheimer's disease (AD)-like pathology. The proposed studies are focused to determine the molecular mechanisms whereby HIV-1 viral protein interacts with the pathogenesis of Alzheimer's disease. The results are expected to provide us with new targets and rationale for preventative and therapeutic interventions against HAND and AD, thus the outcome of the proposed studies could have a substantial impact economically, socially and clinically.