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

描述（由申请人提供）：3-分泌酶BACE1产生与阿尔茨海默病（AD）有关的A -肽。抑制BACE1对阿尔茨海默病中高耸的A¿应该是有效的，然而，BACE1敲除小鼠的记忆和情绪缺陷表明，BACE1抑制可能有副作用。BACE1水平在阿尔茨海默病中升高，提示BACE1升高可能在阿尔茨海默病中发挥作用。我们的研究表明，急性能量抑制使Tg2576小鼠大脑中的BACE1升高，我们的研究结果表明，慢性能量抑制使Tg2576的淀粉样蛋白增加。我们还在阿尔茨海默病Tg2576和我们新的快速淀粉样蛋白模型5XFAD小鼠中观察到斑块周围BACE1升高。BACE1的升高并不是BACE1 mRNA水平升高的结果，这提示了一种转录后机制。两个重要的问题出现了：1)BACE1升高是否与AD的进展有关？2) BACE1升高的分子机制是什么？我们将结合对人类阿尔茨海默病、小鼠阿尔茨海默病和细胞培养的分子、细胞和基因分析来解决这些问题。首先，我们将确定BACE1升高在阿尔茨海默病中的分子谱。然后，AD小鼠将作为BACE1升高的体内模型，细胞培养将用于解剖分子机制。然后，我们将回到人类阿尔茨海默病来验证其机制，并使用AD小鼠作为实验系统来干扰该机制，阻断BACE1的升高，并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BACE1和A¿持续低水平增加，从而驱动AD的发病机制。目的1：确定bace1阳性斑块的分子谱，并检查其与淀粉样蛋白、临床AD和临近死亡时评估的认知功能水平的关系。目的2：确定APR转基因小鼠BACE1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。AIM3：确定体外BACE1升高的分子机制和途径。目的4：验证bace1在阿尔茨海默病和APR转基因脑中的升高分子通路，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进展。阿尔茨海默病是导致老年人痴呆的主要原因，目前尚无治愈方法。随着人口老龄化，阿尔茨海默病的发病率将会增加，预示着阿尔茨海默病的流行即将到来。抑制BACE1升高应能在不直接阻断BACE1的情况下降低A¿，因此对阿尔茨海默病可能有效且无副作用。

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.