Beta-amyloid Modulation: Role of BACE1/BACE2

描述（由申请人提供）：尽管我们对阿尔茨海默病（AD）发病机制的理解取得了重大进展，但由于目前只有对症治疗这种毁灭性疾病，因此缺乏有效的基于机制的治疗方法。“淀粉样蛋白级联假说”强有力的实验支持导致了旨在减少A¿肽（特别是A¿42）的产生或增加其清除率作为治疗AD的潜在治疗策略的强烈努力。由于A -肽是通过-淀粉样蛋白前体蛋白（APP）由-分泌酶和？因此，这两种酶在减轻AD患者A -淀粉样变性的药物开发中具有很高的优先目标。BACE1作为分泌酶的发现刺激了激烈的药物发现研究项目，以确定该酶的药理学抑制剂。虽然BACE1作为一种有吸引力的AD治疗靶点的实验验证已经取得了重大进展，但与髓鞘形成、认知和精神病功能相关的关键BACE1相关信号通路的鉴定引起了人们对这种天冬氨酸蛋白酶的药理抑制相关的潜在机制毒性的关注。因此，进一步评估BACE1的生理作用，特别是其在衰老过程中的影响，对开发安全有效的阿尔茨海默病治疗方法具有重要价值。我们计划解决与BACE1活性降低相关的潜在机制毒性问题。我们将首先定义神经系统中BACE1水平降低对1)髓鞘形成、2)认知和3)精神/情绪改变的潜在影响，并验证BACE1的适度降低限制了与BACE1减少相关的潜在机制毒性的假设（Specific Aim 1）。其次，利用BACE1缺失小鼠的神经元培养物，我们计划研究BACE1依赖性NGR1-ErbB4信号的调控及其对突触功能的影响（Specific Aim 2）。由于尚不清楚BACE1缺失小鼠中观察到的低髓鞘化和精神病症状是否由于发育过程中缺乏BACE1，我们计划通过我们的条件BACE1转基因小鼠模型在衰老过程中下调BACE1，来验证BACE1在成年期和衰老过程中缺失不会导致包括低髓鞘化和精神病症状在内的异常表型的假设（Specific Aim 3）。这些拟议的研究将批判性地评估与药物抑制BACE1相关的潜在机制为基础的副作用，旨在改善A¿淀粉样变性，并对设计抗BACE1治疗AD具有重要意义。公共卫生相关性：在过去几年中，阿尔茨海默病（AD）治疗的药物靶点鉴定取得了重大进展，包括发现BACE1作为AD中涉及的2-分泌酶，以及随后该酶作为这种老年人毁灭性疾病的有吸引力的治疗靶点的验证。由于BACE1在大脑中发挥的重要作用，药理抑制BACE1可能与不良副作用有关。因此，我们将利用我们的一系列转基因BACE1小鼠模型来批判性地评估BACE1的神经生物学，特别是其在衰老过程中的影响，以努力开发安全有效的阿尔茨海默病治疗方法。

DESCRIPTION (provided by applicant): Despite significant advances made toward our understanding of the pathogenesis of Alzheimer's disease (AD), effective mechanism-based therapies are lacking as only symptomatic treatments for this devastating illness are currently available. Strong experimental support of the "amyloid cascade hypothesis" has led to intense efforts aimed at decreasing the generation of A¿ peptides (especially A¿42) or increasing their clearance as potential therapeutic strategies for the treatment of AD. Since A¿ peptides are generated through sequential processing of the ¿-amyloid precursor protein (APP) by ¿-secretase and ?-secretase, these two enzymes represent high priority targets for drug discoveries in efforts to attenuate A¿ amyloidosis in AD. The discovery of BACE1 as the ¿-secretase stimulated intense drug discovery research programs to identify pharmacological inhibitors of the enzyme. While significant advances in experimental validation of BACE1 as an attractive therapeutic target for AD has been made, the identification of critical BACE1- associated signaling pathways linked to myelination, cognition and psychotic functions raise concerns regarding the potential mechanism-based toxicities associated with pharmacological inhibition of this aspartyl protease. Therefore, further evaluation of the physiological roles of BACE1, particularly its impact during aging should be of great value towards the development of safe and effective treatment for AD. We plan to address the issue of potential mechanism-based toxicities associated with decrease in BACE1 activity. We will first define the potential liabilities of reducing level of BACE1 in the nervous system on 1) myelination, 2) cognition and 3) psychotic/emotional alterations and to test the hypothesis that moderate reduction of BACE1 limits the potential mechanism-based toxicity associated with reduction of BACE1 (Specific Aim 1). Secondly, taking advantage of neuronal cultures derived from BACE1 null mice, we plan to study the regulation of BACE1- dependent NGR1-ErbB4 signaling and its effects on synaptic function (Specific Aim 2). Because it is not known whether hypomyelination and psychotic symptoms observed in BACE1 null mice are due to the lack of BACE1 during development, we plan in to test the hypothesis that deletion of BACE1 in adulthood and during aging does not lead to abnormal phenotypes, including hypomyelination and psychotic symptoms, using our conditional BACE1 transgenic mouse model to down regulate BACE1 during aging (Specific Aim 3). These proposed studies will critically evaluate the potential mechanism-based side effects associated with pharmacological inhibition of BACE1 aimed at amelioration of A¿ amyloidosis and have important implications for design of anti-BACE1 therapy for AD. PUBLIC HEALTH RELEVANCE: Significant advances in identification of drug targets for Alzheimer's disease (AD) therapy have been made over the past several years, including the discovery of BACE1 as the 2-secretase involved in AD and the subsequent validation of this enzyme as an attractive therapeutic target for this devastating disease of the elderly. Because of the important roles that BACE1 play in the brain, it is plausible that pharmacological inhibition of BACE1 is associated with untoward side effects. Therefore, we will take advantage of our series of genetically altered BACE1 mouse models to critically evaluate the neurobiology of BACE1, particularly its impact during aging, in efforts towards the development of a safe and effective treatment for AD.