BACE1 in neurodegeneration and neurological dysfunction

摘要 阿尔茨海默病(AD)是最常见的年龄依赖性神经退行性疾病 突触和认知功能进行性损害的疾病早期发生 病程。在过去的三十年里，各种假说被提出 确定AD发病原因。淀粉样蛋白假说受到的检验最多。 在该领域得到了广泛的应用，因为人类基因和 流行病学研究。假说的主要实质是β的异常水平- 淀粉样多肽(Aβ)导致一系列的病理发展，最终导致 阿尔茨海默病患者可能存在突触和认知功能障碍。始终如一地删除或 唯一分解淀粉样前体蛋白(APP)的酶BACE1的抑制 在β分泌酶位置启动Aβ的产生，减少Aβ的产生和淀粉样蛋白 病理学。脑穿透性抑制剂在临床试验中进行了测试，但未能改善 阿尔茨海默病患者的认知功能，导致临床试验提前终止。我们 其他研究表明，BACE1调节突触可塑性和临床应用 在临床测试的剂量下，抑制剂实际上会损害突触功能。在这份提案中， 我们的目标是找到解决方案，利用这种斑块减少的优势，并能够 克服与认知恶化相关的不良副作用 函数/分数。我们的目标是开发一种策略，改善脑内突触功能 AD患者BACE1抑制的相关性研究我们将测试我们的中心假设 如果BACE1介导突触，BACE1抑制剂将更有效地治疗AD 损害在可控范围内。我们提出了两个具体的目标来检验我们的假设： 1是区分毒性Aβ和BACE1介导的突触损伤。 老鼠模型。目的2是确定mGluR1正变构调节剂是否会 改善AD和BACE1介导的突触损伤。最终目标是优化 使用BACE1抑制剂并补充阳性突触增强剂等 代谢型谷氨酸受体-1(MGluR1)变构调节剂在AD小鼠中的作用 我们的初步研究支持改善了BACE1的长时程增强-Null 用mGluR1PAM治疗的小鼠。通过这项研究获得的知识将指导 BACE1在人体中的临床应用前景

Abstract Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disease with progressive impairment in synaptic and cognitive functions occurred early in the disease course. For past three decades, various hypotheses are proposed to determine the cause of AD pathogenesis. The amyloid hypothesis is being tested most extensively in the field because of strong supports from human genetic and epidemiological studies. The main essence of hypothesis is that the abnormal level of β- amyloid peptide (Aβ) leads to sequential pathological developments that eventually cause a potential of synaptic and cognitive dysfunctions in AD patients. Consistently, deletion or inhibition of BACE1, which is a sole enzyme for cleaving amyloid precursor protein (APP) at the β-secretase site to initiate the generation of Aβ, reduces Aβ production and amyloid pathology. Brain penetrable inhibitors are tested in clinical trials but fail to improve cognitive functions in AD patients, resulting in the early termination of clinical trials. We and others show that BACE1 regulates synaptic plasticity and clinical used BACE1 inhibitors actually impair synaptic function at a clinically tested dose. In this proposal, we aim to find solutions that will take the advantage of this plaque reduction and can overcome the unwanted side effects associated with worsening cognitive functions/scores. Our goal is to develop strategy that improve synaptic functions in association with BACE1 inhibition in AD patients. We will test our central hypothesis that BACE1 inhibitors will be more effective for AD treatment if BACE1-mediated synaptic impairment is under controls. Two specific aims are proposed to test our hypothesis: Aim 1 is to differentiate toxic Aβ-mediated and BACE1-mediated synaptic impairments in mouse models. Aim 2 is to determine whether mGluR1 positive allosteric modulator will improve AD and BACE1-mediated synaptic impairment. The ultimate goal is to optimize the use of BACE1 inhibitors and supplement with synaptic enhancer such as a positive allosteric modulator (PAM) of metabotropic glutamate receptor-1 (mGluR1) in AD mice. Our preliminary studies support shows improved long term potentiation in BACE1-null mice treated with an mGluR1 PAM. Knowledge gained from this study will guide the future clinical application of BACE1 in human.