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

描述(由申请人提供)： 在我们对HIV-1如何与阿尔茨海默病(AD)的发病机制相互作用的理解上存在着根本的差距，确定其潜在的机制是我们的长期目标。拟议研究的目的是确定转录反式激活因子(TAT)的分子机制，TAT是一种艾滋病毒-1病毒蛋白，继续与 HIV-1相关性神经认知障碍(HAND)的发病机制最近被认为与AD样病理的发展有关，增加了神经元A？一代。我们的中心假设是TAT增加了神经元内的A？通过促进APP内化和提高内溶酶体pH来产生。在我们初步发现的指导下，这一新的、未经检验的假设将通过追求两个具体目标来检验：(1)确定TAT促进APP内部化的机制，从而提高APP的处理能力，有利于A？制作。(2)确定TAT提高内溶酶体pH从而增强BACE-1活性从而有利于A？制作。Aim#1中提出的工作结果有望证明LRP-1是HIV-1蛋白诱导的APP内化增加的原因，并且LRP-1的siRNA敲除可以阻止HIV-1蛋白诱导的神经元内A？制作。AIM#2的结果有望证明，质子依赖的多肽转运体Pept2是TAT诱导的内溶酶体pH升高的原因，而Pept2的siRNA敲除可阻止TAT诱导的内溶酶体pH升高，增加BACE-1的内溶酶体积聚，增强BACE-1的活性，并增加神经细胞内A？制作。这些结果有望为我们预防和治疗HAND和AD提供新的靶点和理论基础。因此，拟议研究的结果可能会在经济、社会和临床上产生重大影响。 公共卫生相关性： 这项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)的高患病率和发展为阿尔茨海默病(AD)样病理的增加。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。这些结果有望为我们预防和治疗HAND和AD提供新的靶点和理论基础，因此拟议的研究结果可能会在经济、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.