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 共激活剂 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还影响与阿尔茨海默病 (AD) 淀粉样蛋白神经病理学相关的机制。在支持退伍军人事务部 (VA) 优异申请的正在进行的可行性研究中，我们发现 PGC-1a 在促进 F-box2-E3 连接酶 (Fbx2) 介导的 2-分泌酶 (BACE1) 泛素化中发挥着至关重要的作用。该作用最终导致 BACE1 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 BACE1 联系起来的机制证据，而 BACE1 影响 AD 淀粉样蛋白神经病理学。本申请中提出的研究的工作假设是，在 AD 大脑中表达受损的 PGC-1a 可以协同 Fbx2 并促进泛素化，最终导致 BACE1 降解。 BACE1 是预防 AD 淀粉样蛋白生成的一个有吸引力的靶标，因为大脑中 BACE1 表达的减少阻止了通过淀粉样前体蛋白 (APP) 的特异性裂解产生的淀粉样蛋白 A 肽的生成。本研究旨在探讨 PGC-1a 在 Fbx2 连接酶介导的 BACE1 蛋白酶体降解中的机制作用。此外，我们将在小鼠模型中探讨 Fbx2 在减轻 AD 型淀粉样蛋白神经病理学和认知恶化中的功能作用。我们提出的研究将为探索 PGC-1a 在 AD 淀粉样蛋白神经病理学实验模型中的机制作用提供前所未有的机会。这将使我们最终能够找到通过 PGC-1a 介导的反应来预防或减轻 AD 表型的新方法，并将其转化为 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.