Muscarinic Acetylcholine Receptors and Alzheimer's Disease Pathogenesis

毒蕈碱乙酰胆碱受体与阿尔茨海默病发病机制

• 批准号: 7275487
• 负责人: Albert A Davis
• 金额: $ 3.02万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275487
• 关键词: Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavioral; Biochemical Genetics; Biological; Brain; Cells; Cholinergic Agents; Cognition; Coupled; Dementia; Development; Disease; Disease Progression; Effectiveness; Elderly; Emotions; Enzymes; Event; Family; Health; Histological Techniques; Individual; Knock-out; Knockout Mice; Measures; Mediating; Memory Loss; Modeling; Molecular; Motor Activity; Mus; Muscarinic Acetylcholine Receptor; Muscarinic M1 Receptor; Neuraxis; Neurons; Neurotransmitters; Pan Genus; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Production; Proteolysis; Proteolytic Processing; Range; Regulation; Reporting; Role; Senile Plaques; Signal Transduction; Signal Transduction Pathway; Societies; System; Testing; Therapeutic; Thinking; Transgenic Mice; Transgenic Organisms; alpha secretase; amyloid pathology; amyloid peptide; amyloid precursor protein processing; amyloidogenesis; base; cholinergic; cholinergic neuron; clinical efficacy; cognitive function; human CHRM1 protein; human disease; in vivo Model; insight; interest; intracellular protein transport; mouse model; nervous system disorder; neurotransmission; protein transport; receptor; secretase; therapy design

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.

描述（由申请人提供）：中央胆碱能神经递质系统与阿尔茨海默氏病（AD）之间的关系继续深入了解这种毁灭性疾病的病理基础。胆碱能神经元在AD中丢失，并且旨在增强胆碱能功能的药理疗法显示出一些适度的临床功效。胆碱能神经传递的部分是由五个类似但独特的毒蕈碱乙酰胆碱受体（M1-M5 MACHR）的家族介导的。 MACHR亚型似乎差异地调节了淀粉样蛋白前体蛋白（APP）的加工，淀粉样蛋白（APP）是AD病理生物学中的关键分子，通过蛋白水解处理引起了A-beta肽，但单个MACHR子类型对AD的发展和进展的精确贡献仍然是不完全理解的。在这项研究中，我们建议使用遗传，生化和组织学技术的组合来定义负责调节AD病理学的毒蕈碱受体的分子亚型。基于先前的报告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的非淀粉样生成处理并限制了疾病的进展，而M2和/或M4亚型可能会加速APP的淀粉样蛋白生成处理。在AIM 1中，我们将利用来自MACHR亚型缺乏小鼠的主要神经元培养物来评估MACHR信号在应用程序处理中的作用。我们假设M1受体的丧失将增加淀粉样蛋白生成的应用程序处理，而M2和/或M4受体的损失可能会限制淀粉样蛋白生成的应用程序处理。在AIM 2中，我们将通过将M1 MACHR敲除（KO）小鼠与AppSWE/IND转基因鼠标模型跨越M1 MACHR敲除（KO）小鼠，将AIM 1的机械发现扩展到AD的体内模型中。我们假设与M1（+/+）同窝仔相比，与M1 KO小鼠交叉的APPSWE/IND小鼠将显示出更严重和加速的淀粉样病理学。 AIM 3将研究APP处理的MACHR亚型调节的分子机制，假设M1激活诱导Adam 17. Adam 17.阿尔茨海默氏病（AD）的激活和易位是老年人痴呆症的主要原因（AD），这是老年人和这种持续增长的繁荣，并且具有成熟的繁荣，并且既繁荣又具有成果。通过研究毒蕈碱乙酰胆碱受体与AD根本原因的关系，本研究试图增加这种毁灭性疾病的分子理解和潜在的治疗途径。