Mechanisms of BACE1 Degradation in Experimental Alzheimer's Disease Therapeutic

描述（由申请人提供）： 拟议研究的总体目标是继续研究过氧化物酶体增殖物激活受体-3共激活因子-1a（PGC-1a）的新特征。该基因与糖尿病有关，我们最近发现该基因也影响与阿尔茨海默病（AD）淀粉样神经病理学相关的机制。在正在进行的支持退伍军人事务部（VA）Merit申请的可行性研究中，我们发现PGC-1a在促进F-box 2-E3连接酶（Fbx 2）介导的2-分泌酶（BACE 1）泛素化中起着至关重要的作用。这种作用最终导致BACE 1通过泛素蛋白酶体系统（UPS）降解。我们的研究结果提供了可能将PGC-1a与BACE 1联系起来的机制证据，BACE 1影响AD淀粉样神经病理学。本申请中提出的研究的工作假设是，在AD脑中表达受损的PGC-1a可以协同Fbx 2并促进泛素化，最终导致BACE 1的降解。BACE 1是预防AD淀粉样蛋白生成的一个有吸引力的靶点，因为BACE 1在脑中表达的减少排除了通过特异性裂解淀粉样前体蛋白（APP）产生的淀粉样蛋白生成A肽的产生。本研究旨在探讨PGC-1a在Fbx 2连接酶介导的BACE 1蛋白酶体降解中的作用机制。此外，我们将探索Fbx 2在小鼠模型中AD型淀粉样蛋白神经病理学和认知退化的衰减中的功能作用。我们提出的研究将为探索PGC-1a在AD-淀粉样神经病理学实验模型中的机制作用提供前所未有的机会。这将使我们能够最终确定通过PGC-1a介导的反应预防或减轻AD表型的新方法，这些反应可以转化为AD疗法。

DESCRIPTION (provided by applicant): The overall goal of the proposed studies is to continue investigating a novel feature of peroxisome proliferator- activated receptor-3 coactivator-1a (PGC-1a). This gene has been implicated in diabetes, and we recently found that this gene also influences mechanisms associated with Alzheimer's disease (AD) amyloid neuropathology. In the ongoing feasibility studies supporting this Department of Veterans Affairs (VA) Merit application, we found that PGC-1a plays a crucial role in promoting F-box2-E3 ligase (Fbx2) mediated 2-secretase (BACE1) ubiquitination. This role ultimately leads to BACE1 degradation through the ubiquitin proteasome system (UPS). Our findings provide mechanistic evidence that could possibly link PGC-1a to BACE1, which influences AD amyloid neuropathology. The working hypothesis for the studies proposed in this application is that PGC-1a, whose expression is impaired in the AD brain, can synergize Fbx2 and promote ubiquitination that eventually leads to the degradation of BACE1. BACE1 is an attractive target for preventing AD amyloidogenesis because the reduction of BACE1 expression in the brain precludes the generation of amyloidogenic A¿ peptides produced through specific cleavages of the amyloid precursor protein (APP). The present studies were designed to explore the mechanistic role of PGC-1a in the Fbx2 ligase-mediated proteasomal degradation of BACE1. Furthermore, we will explore the functional role of Fbx2 in the attenuation of AD-type amyloid neuropathology and cognitive deterioration in mouse models. Our proposed studies will provide an unprecedented opportunity to explore the mechanistic role of PGC-1a in experimental models of AD-amyloid neuropathology. This will allow us to eventually identify novel approaches to prevent or attenuate AD phenotypes through PGC-1a-mediated responses that could be translated into AD therapies.