Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function

γ-分泌酶和 ApoE 对胆固醇的调节：对 AD 发病机制和突触功能的影响

• 批准号: 10601030
• 负责人: Thomas C. Sudhof
• 金额: $ 76.3万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601030
• 关键词: Abeta synthesis; Adopted; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; American; Amyloid; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Apolipoprotein E; Behavior; Brain; Cells; Cellular biology; Cholesterol; Cholesterol Homeostasis; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cytoplasmic Protein; Dementia; Disease; Disease Progression; Early Onset Familial Alzheimer' s Disease; Electrophysiology (science); Functional disorder; Future; Genes; Genetic; Genetic Transcription; Genetic study; Human; Impaired cognition; Impairment; Induced Mutation; Inflammatory Response; Knockout Mice; Link; Lipids; Measurement; Mediating; Membrane Proteins; Microglia; Mus; Mutation; Nature; Neurodegenerative Disorders; Neuroglia; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Preparation; Property; Protein Fragment; Regulation; Role; Sampling; Signal Transduction; Societies; Synapses; Synaptic Transmission; TREM2 gene; Techniques; Testing; Therapeutic; Therapeutic Intervention; United States; Up-Regulation; Variant; abeta accumulation; amyloid formation; apolipoprotein E-4; drug development; electrical property; experimental study; familial Alzheimer disease; gamma secretase; genetic variant; in vivo; induced pluripotent stem cell; insight; interdisciplinary approach; lipid metabolism; lipid transport; mouse model; neural circuit; neuron loss; notch protein; novel; pharmacologic; presenilin; presenilin-1; prevent; risk variant; secretase; synaptic failure; synaptic function; transcriptome sequencing; transcriptomics

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the United States that affects more than 5 million Americans. Synapses are the earliest affected component of the brain during AD pathogenesis, suggesting that the cognitive decline and neuronal loss in AD initiates with synaptic dysfunction. Despite much effort, however, no definitive understanding of AD pathogenesis is available, and no therapies that alleviate or even stop progression of AD are known. Genetic studies identified rare mutations in presenilin and in APP genes that cause early-onset familial AD (FAD), and described common variants in several genes, chiefly the ApoE and TREM2 genes, that predispose to sporadic AD, providing potential clues to AD pathogenesis. Presenilin mutations impair the activity of γ-secretase, an intramembranous protease that cleaves a large number of membrane proteins, including APP. Presenilin and APP mutations associated with FAD both enhance production of Aβ, a cleavage product of APP. Moreover, all AD patients suffer from an accumulation of Aβ in brain, leading to the `amyloid Aβ hypothesis' whereby AD is induced by Aβ amyloid accumulation in brain. However, therapies that prevent or even reverse Aβ accumulation in brain have not been effective in treating AD. Furthermore, ApoE and TREM2 are not directly related to Aβ, but seem to influence microglial function, inflammatory responses, and/or lipid metabolism. Indeed, alterations in lipid content are a prominent feature of AD brains, suggesting that Aβ may be related to AD pathogenesis in a manner that is not related to amyloid formation. Indeed, in preliminary experiments we observed that a chronic decrease γ-secretase activity, as would be observed with FAD- associated mutations of presenilin genes, causes a major decrease in synaptic transmission and an upregulation of cholesterol synthesis. Based on the all of these findings together, we here propose an interdisciplinary project that examines the role of changes in γ-secretase activity in synaptic function and lipid metabolism as a potential pathogenetic mechanism in AD. We describe four specific aims that will investigate the relationship of γ- secretase to synaptic transmission, the mechanism by which γ-secretase activity normally suppresses cholesterol synthesis, and the possibility that increased cholesterol synthesis induced by a chronic decrease in γ-secretase activity is responsible for the observed synaptic impairments. Moreover, the proposed specific aims will explore the possibility that ApoE4, the ApoE variant predisposing to AD, also acts by altering lipid metabolism in neurons. These experiments will adopt a multidisciplinary approach that will be carried out in human neurons and in mouse brains, and will combine cell biology, transcriptomics, CRISPR, and electrophysiology techniques to explore the underlying mechanisms. Among others, these experiments will contribute to our understanding of how presenilin mutations that cause FAD and impair γ-secretase activity affect synapses, and test the overall hypothesis that FAD-associated presenilin mutations and genetic ApoE variants predisposing to sporadic AD act by a sucommon pathway regulating neuronal cholesterol levels, which in turn influences synaptic function.

阿尔茨海默氏病（AD）是美国最常见的神经退行性疾病 超过500万美国人。突触是AD发病机理期间最早的大脑影响成分， 表明AD的认知能力下降和神经元丧失具有突触功能障碍。尽管很多 但是，努力没有对AD发病机理的明确理解，也没有减轻或 甚至已知停止AD的进展。遗传研究确定了老年蛋白和APP基因中的罕见突变 这会引起早发的家族广告（FAD），并描述了几种基因的常见变体，主要是ApoE 和Trem2基因，易于散发AD，为AD发病机理提供了潜在的线索。 presenilin 突变会损害γ-分泌酶的活性，γ-分泌酶是一种裂解大量的膜内蛋白酶 膜蛋白，包括应用。与FAD相关的Presenilin和App突变都可以增强生产 Aβ，App的乳沟产物。此外，所有AD患者都遭受大脑中Aβ的积累，领先 对于“淀粉样蛋白Aβ假说”，AD是由Aβ淀粉样蛋白在大脑中诱导的。但是，疗法 预防甚至逆转大脑中的Aβ积累尚未有效治疗AD。此外，Apoe 和TREM2与Aβ没有直接相关，但似乎会影响小胶质功能，炎症反应， 和/或脂质代谢。实际上，脂质含量的改变是广告大脑的重要特征，表明 Aβ可能以与淀粉样形成无关的方式与AD发病机理有关。确实，在初步 实验我们观察到慢性降低γ-分泌酶活性，如FAD-所观察到的那样 寄生虫基因的相关突变会导致突触传播的主要减少和上调 胆固醇合成。根据所有这些发现，我们在这里提出了一个跨学科项目 这检验 AD中的致病机制。我们描述了将研究γ-的关系的四个特定目标 突触传播的泌尿酶，γ-分泌酶活性通常抑制的机制 胆固醇的合成以及增加胆固醇合成的可能性 γ-分泌酶活性负责观察到的突触障碍。而且，拟议的特定目标 将探索ApoE4（ApoE变体易于AD）的可能性，也可以通过改变脂质代谢来起作用 在神经元中。这些实验将采用一种多学科的方法，该方法将在人类神经元中进行 在小鼠大脑中，将结合细胞生物学，转录组学，CRIS和电生理技术 探索潜在的机制。除其他外，这些实验将有助于我们的理解 导致FAD并损害γ-分泌酶活性的Presenilin突变如何影响突触，并测试整体 假设易于散发性AD ACT的假设是FAD相关的presenilin突变和遗传APOE变体 通过调节神经元胆固醇水平的Sucommon途径，这反过来影响突触功能。