Molecular Neuropathology and Mechanisms of BACE1 Elevation in Alzheimer's Disease

描述（由申请人提供）：3-分泌酶BACE 1产生参与阿尔茨海默病（AD）的A肽。抑制BACE 1对阿尔茨海默病中高耸的A？应该是有效的，然而BACE 1敲除小鼠的记忆和情感缺陷表明BACE 1抑制可能有副作用。BACE 1水平在阿尔茨海默病中增加，表明BACE 1升高可能在阿尔茨海默病中起作用。我们已经表明，急性能量抑制提高BACE 1和Tg 2576小鼠的大脑中，我们的结果表明，慢性能量抑制增加Tg 2576中的淀粉样蛋白。我们还观察到阿尔茨海默病Tg 2576和我们新的快速淀粉样蛋白模型5XFAD小鼠中斑块周围的BACE 1升高。BACE 1升高不是BACE 1 mRNA水平增加的结果，表明存在转录后机制。出现了两个重要问题：1）BACE 1升高是否与AD进展有关？2)BACE 1升高的分子机制是什么？我们将通过对人类阿尔茨海默病、小鼠阿尔茨海默病和细胞培养物的分子、细胞和遗传分析来解决这些问题。首先，我们将确定阿尔茨海默病中BACE 1升高的分子特征。然后将AD小鼠用作BACE 1升高的体内模型，并将使用细胞培养物来剖析分子机制。然后，我们将回到人类阿尔茨海默病来验证机制，并使用AD小鼠作为实验系统来干扰机制，阻断BACE 1升高，改善淀粉样蛋白病理和记忆缺陷。我们的总体假设是，AD期间的慢性细胞应激导致BACE 1和A？的持续低水平增加，从而驱动AD发病机制。目标1：确定BACE 1阳性斑块的分子特征，并检查其与淀粉样蛋白和临床AD的关系以及接近死亡时评估的认知功能水平。目标2：确定APR转基因小鼠中BACE 1随年龄升高的分子和细胞特征，并与人类阿尔茨海默病进行比较。目的3：确定BACE 1在体外升高的分子机制和途径。目标4：研究阿尔茨海默病和APR转基因脑中BACE 1升高分子通路，并确定在APR转基因小鼠中抑制该通路是否会减缓淀粉样蛋白病理学的进展。阿尔茨海默病是老年痴呆症的主要原因，目前还没有治愈的方法。老年痴呆症的发病率将因人口老龄化而增加，预示着AD流行即将到来。BACE 1升高的抑制应该在不直接阻断BACE 1的情况下降低A β，因此可能对阿尔茨海默病有效而无副作用。

DESCRIPTION (provided by applicant): 3-Secretase BACE1 generates the A¿ peptide involved in Alzheimer's disease (AD). Inhibition of BACE1 for towering A¿ in Alzheimer's disease should be efficacious, however memory and emotional deficits in BACE1 knockout mice suggest that BACE1 inhibition may have side-effects. BACE1 levels are increased in Alzheimer's disease, suggesting that BACE1 elevation may play a role in Alzheimer's disease. We have shown that acute energy inhibition elevates BACE1 and in brains of Tg2576 mice, and our results indicate that chronic energy inhibition increases amyloid in Tg2576. We also observe elevated BACE1 around plaques in Alzheimer's disease, Tg2576, and in our new rapid amyloid model, 5XFAD mice. BACE1 elevation is not the result of increased BACE1 mRNA levels, suggesting a post- transcriptional mechanism. Two important questions arise: 1) Is BACE1 elevation involved in AD progression? 2) What is the molecular mechanism of BACE1 elevation? We will address these questions using a combination of molecular, cellular, and genetic analyses of human Alzheimer's disease, mouse Alzheimer's disease, and cell cultures. First, we will determine the molecular profile of BACE1 elevation in Alzheimer's disease. AD mice will then serve as in vivo models of BACE1 elevation, and cell cultures will be used to dissect molecular mechanism. We will then return to human Alzheimer's disease to verify the mechanism and use AD mice as experimental systems to interfere with the mechanism, block BACE1 elevation, and ameliorate amyloid pathology and memory deficits. Our overall hypothesis is that chronic cellular stress during AD results in sustained low-level increases of BACE1 and A¿ that drive AD pathogenesis. AIM1: Determine the molecular profile of BACE1-positive plaques, and examine their relation to amyloid and to clinical AD and level of cognitive function assessed proximate to death. Aim2: Determine the molecular and cellular characteristics of the BACE1 elevation with age in APR transgenic mice and compare to human Alzheimer's disease. AIM3: Determine the molecular mechanism and pathway of the BACE1 elevation in vitro. Aim4: Validate the BACE1-elevating molecular pathway in Alzheimer's disease and APR transgenic brain and determine whether inhibition of the pathway in APR transgenic mice will slow progression of amyloid pathology. Alzheimer's disease is the leading cause of dementia in the elderly and there is no cure. The incidence of Alzheimer's disease will increase due to the aging population, indicating an impending AD epidemic. Inhibition of BACE1 elevation should reduce A¿ without directly blocking BACE1 and thus may be efficacious without side-effects for Alzheimer's disease.