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）：中枢胆碱能神经递质系统和阿尔茨海默病（AD）之间的关系继续提供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，旨在增强胆碱能功能的药物治疗显示出一定的临床疗效。胆碱能神经传递部分由一个由五种类似但不同的毒蕈碱乙酰胆碱受体（M1-M5 mAChR）组成的家族介导。mAChR亚型似乎差异调节淀粉样前体蛋白（APP）的加工，APP是AD病理生物学中的关键分子，通过蛋白水解加工产生A-β肽，但单个mAChR亚型对AD发生和进展的精确贡献仍不完全清楚。在这项研究中，我们建议使用遗传学，生物化学和组织学技术相结合，以确定负责调制AD病理的毒蕈碱受体的分子亚型。基于以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APP的非淀粉样蛋白加工和限制疾病的进展，而M2和/或M4亚型可能加速APP的淀粉样蛋白加工。在目的1中，我们将利用原代神经元培养缺乏mAChR亚型的小鼠，以评估mAChR信号转导对APP加工的作用。我们假设M1受体的缺失将增加淀粉样蛋白生成APP的加工，而M2和/或M4受体的缺失可能限制淀粉样蛋白生成APP的加工。在目的2中，我们将通过将M1 mAChR敲除（KO）小鼠与APPswe/ind转基因小鼠模型交叉，将目的1的机制研究结果扩展到AD的体内模型中。我们假设与M1 KO小鼠杂交的APPswe/ind小鼠与M1（+/+）同窝小鼠相比，将显示更严重和加速的淀粉样蛋白病理学。目的3将研究潜在的mAChR亚型调节APP加工的分子机制，假设M1激活诱导α-分泌酶候选人ADAM 17的激活和易位。阿尔茨海默氏病（AD）是老年痴呆症的主要原因，因此，对我们社会的健康和繁荣造成了巨大且持续增长的负担。通过研究毒蕈碱型乙酰胆碱受体与AD潜在病因的关系，本研究旨在增加对这种毁灭性疾病的分子认识和潜在治疗途径。