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）的发病机制的理解取得了重大进展，但缺乏有效的基于机制的治疗，因为目前只有针对这种毁灭性疾病的对症治疗。对“淀粉样蛋白级联假说”的强有力的实验支持已经导致了旨在减少A肽（特别是A肽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β-分泌酶和β-淀粉样前体蛋白（APP）的连续加工产生的，分泌酶，这两种酶代表了药物发现的高度优先目标，以减轻AD中的淀粉样变性。BACE 1作为β-分泌酶的发现刺激了激烈的药物发现研究计划，以确定该酶的药理学抑制剂。虽然BACE 1作为AD的有吸引力的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BACE 1相关信号通路的鉴定引起了人们对与这种乙酰基蛋白酶的药理学抑制相关的潜在机制毒性的担忧。因此，进一步评估BACE 1的生理作用，特别是其在衰老过程中的影响，对于开发安全有效的AD治疗方法具有重要价值。我们计划解决与BACE 1活性降低相关的潜在机制毒性问题。我们将首先定义降低神经系统中BACE 1水平对1）髓鞘形成、2）认知和3）精神病/情绪改变的潜在不利影响，并检验BACE 1中度降低限制与BACE 1降低相关的潜在机制毒性的假设（具体目标1）。其次，利用来自BACE 1敲除小鼠的神经元培养物，我们计划研究BACE 1依赖性NGR 1-ErbB 4信号传导的调节及其对突触功能的影响（具体目标2）。由于尚不清楚在BACE 1缺失小鼠中观察到的髓鞘形成不足和精神病症状是否是由于发育期间缺乏BACE 1所致，因此我们计划使用我们的条件性BACE 1转基因小鼠模型在衰老期间下调BACE 1来检验以下假设：在成年期和衰老期间缺失BACE 1不会导致异常表型，包括髓鞘形成不足和精神病症状（具体目标3）。这些拟议的研究将严格评估与旨在改善A淀粉样变性的BACE 1药理学抑制相关的潜在机制副作用，并对AD抗BACE 1治疗的设计具有重要意义。公共卫生相关性：在过去的几年中，阿尔茨海默病（AD）治疗的药物靶点的鉴定取得了重大进展，包括发现BACE 1作为参与AD的2-分泌酶，以及随后验证这种酶作为老年人这种毁灭性疾病的有吸引力的治疗靶点。由于BACE 1在大脑中发挥的重要作用，药物抑制BACE 1与不良副作用相关是合理的。因此，我们将利用我们的一系列基因改变的BACE 1小鼠模型来严格评估BACE 1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AD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.