Muscarinic Acetylcholine Receptors and Alzheimer's Disease Pathogenesis

描述(由申请人提供)：中枢胆碱能神经递质系统与阿尔茨海默病(AD)之间的关系继续提供对这种毁灭性疾病的病理基础的洞察。胆碱能神经元在阿尔茨海默病中丢失，旨在增强胆碱能功能的药物治疗显示出一些适度的临床疗效。胆碱能神经传递部分由5个相似但不同的M受体家族(M1-M5 mAChRs)介导。MAChR亚型似乎对淀粉样前体蛋白(APP)的加工有不同的调节作用，APP是AD病理生物学中的关键分子，通过蛋白分解加工产生A-β肽，但单个mAChR亚型在AD的发生发展中的确切作用仍不完全清楚。在这项研究中，我们建议结合遗传、生化和组织学技术来确定参与AD病理调控的M受体的分子亚型。根据以前的报道和我们自己的初步证据，我们的中心假设是M1亚型促进了APP的非淀粉样变过程，并限制了疾病的进展，而M2和/或M4亚型可能加速了APP的淀粉样变过程。在目标1中，我们将利用mAChR亚型缺陷小鼠的原代神经元培养来评估mAChR信号在APP处理中的作用。我们假设M1受体的缺失会增加淀粉样变性APP的加工，而M2和/或M4受体的缺失可能会限制淀粉样变性APP的加工。在目标2中，我们将通过将M1 mAChR基因敲除(KO)小鼠与APPswe/ind转基因小鼠模型杂交，将Aim 1的机制发现扩展到AD的体内模型中。我们推测，与M1(+/+)小鼠相比，APPswe/ind小鼠与M1 KO小鼠杂交后将表现出更严重和更加速的淀粉样蛋白病理。目的3将研究mAChR亚型调控APP加工的分子机制，假设M1激活诱导α-分泌酶候选者亚当17的激活和易位。阿尔茨海默病(AD)是老年人痴呆的主要原因，因此，对我们的社会的健康和繁荣来说，是一个巨大的且持续增长的负担。通过研究M受体与阿尔茨海默病潜在病因的关系，本研究试图增加对这一毁灭性疾病的分子理解和潜在的治疗途径。

DESCRIPTION (provided by applicant): The relationship between central cholinergic neurotransmitter systems and Alzheimer's disease (AD) continues to offer insight into the pathologic basis of this devastating illness. Cholinergic neurons are lost in AD, and pharmacologic therapies designed to augment cholinergic function show some modest clinical efficacy. Cholinergic neurotransmission is mediated in part by a family of five similar but distinct muscarinic acetylcholine receptors (M1-M5 mAChRs). mAChR subtypes appear to differentially regulate the processing of amyloid precursor protein (APP), a pivotal molecule in AD pathobiology that gives rise to the A-beta peptide via proteolytic processing, but the precise contributions of individual mAChR subtypes to the development and progression of AD remains incompletely understood. In this study, we propose to use a combination of genetic, biochemical, and histologic techniques to define the molecular subtypes of muscarinic receptors responsible for modulating AD pathology. Based on previous reports and our own preliminary evidence, our central hypothesis is that the M1 subtype promotes non-amyloidogenic processing of APP and limits disease progression, while M2 and/or M4 subtypes may accelerate the amyloidogenic processing of APP. In Aim 1, we will make use of primary neuronal cultures from mice deficient in mAChR subtypes to evaluate the role of mAChR signaling on APP processing. We hypothesize that loss of M1 receptors will increase amyloidogenic APP processing, while loss of M2 and/or M4 receptors may limit amyloidogenic APP processing. In Aim 2, we will extend the mechanistic findings of Aim 1 into an in vivo model of AD by crossing M1 mAChR knockout (KO) mice with the APPswe/ind transgenic mouse model. We hypothesize that APPswe/ind mice crossed with M1 KO mice will display more severe and accelerated amyloid pathology as compared to M1 (+/+) littermates. Aim 3 will investigate the molecular mechanisms underlying mAChR subtype regulation of APP processing, with the hypothesis that M1 activation induces the activation and translocation of the alpha-secretase candidate ADAM 17. Alzheimer's disease (AD) is the leading cause of dementia in the elderly and as such, represents an immense and continually growing burden on the health and prosperity of our society. By investigating the relationship of muscarinic acetylcholine receptors to the underlying cause of AD, this study seeks to increase the molecular understanding and potential therapeutic avenues of this devastating illness.