The Role of Gamma-Secretase in Human Neuronal Physiology

γ-分泌酶在人类神经生理学中的作用

• 批准号: 10222551
• 负责人: Sofia Essayan-Perez
• 金额: $ 2.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2022-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222551
• 关键词: Abeta synthesis; Adhesions; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biochemical; CRISPR interference; Catalytic Domain; Cell model; Cells; Chronic; Cleaved cell; Data; Dementia; Development; Electrophysiology (science); Functional disorder; Gene Expression; Genetic; Goals; Human; Immunoblotting; Impairment; In Vitro; Individual; Integral Membrane Protein; Knowledge; Length; Molecular; Morphology; Mus; Mutate; Mutation; Nerve Degeneration; Neuroglia; Neurons; Pathology; Pathway interactions; Peptide Hydrolases; Pharmacology; Physicians; Physiological; Physiology; Pluripotent Stem Cells; Presenile Alzheimer Dementia; Process; Proteins; Quantitative Reverse Transcriptase PCR; Regulation; Role; Scientist; Senile Plaques; Shapes; Signal Transduction; Synapses; Synaptic Transmission; System; Technical Expertise; Techniques; Testing; Training; Transmembrane Domain; United States; Work; aging brain; amyloid precursor protein processing; base; confocal imaging; gamma secretase; imaging modality; inhibitor/antagonist; insight; mouse model; nervous system disorder; normal aging; novel; novel strategies; patch clamp; postsynaptic; presenilin; presynaptic; prevent; relating to nervous system; response; scaffold; secretase; synaptic function; synaptogenesis; therapeutic target; transmission process; vesicular release

Abstract Alzheimer's Disease (AD) is the leading cause of dementia in the United States, affecting 5.7 million Americans, yet no treatments exist. Early-onset AD is most commonly caused by familial mutations of presenilins, the catalytic subunit of the protease g-secretase. Mutated 𝛾-secretase cleaves the amyloid precursor protein (APP) and releases toxic b-amyloid peptides associated with synapse loss. However, 𝛾-secretase may also contribute to synaptic dysfunction in AD through mechanisms beyond APP processing. While 𝛾-secretase contributes to AD pathology, its broader physiological roles in maintaining the proper functioning of human synapses is poorly understood. Evidence from non-neuronal cells and murine models suggest that 𝛾-secretase may process over 90 transmembrane proteins, including synaptic signaling, scaffolding, and adhesion proteins. A knowledge gap exists on how 𝛾-secretase maintains the proper functioning of healthy synapses in human neurons, which can further inform pathoetiologies of AD. The overall objective of this proposal is to examine in human neurons how 𝛾-secretase regulates biochemical, morphological, and functional features of synapses, with and without chronic activity modulation. Preliminary work in human neurons validates that 𝛾-secretase is required for b-amyloid production and cleavage of full-length APP and Neurexin (Nrxn) proteins. Early results show that 𝛾-secretase is necessary for regulating key presynaptic and postsynaptic protein levels, as well as the number of synapses. Aim 1 will characterize the role of 𝛾-secretase in regulating neuronal protein composition, synapse formation, and synaptic transmission to better understand its functions at human synapses. We hypothesize that 𝛾- secretase is needed for maintaining synaptic integrity, through the processing of presynaptic and postsynaptic proteins. Aim 2 will determine how 𝛾-secretase modulates synapses in response to chronic increases or decreases of neural activity. As other proteases have activity-dependent regulation, we hypothesize that 𝛾- secretase regulates synaptic protein composition and synaptic transmission following chronic modulation. Understanding the role of 𝛾-secretase at healthy synapses will provide insight into the physiological synaptic processes regulated by this protease, which will advance our understanding of the normal aging brain and AD pathology. The proposed project will establish the neuronal roles of 𝛾-secretase in a human neuron-specific manner. Further, it will reveal the function of 𝛾-secretase in modulating synaptic activity. Greater insight into proteolytic activity in human neurons will elucidate candidate pathways and potential therapeutic targets for AD.

摘要 阿尔茨海默病（AD）是美国痴呆症的主要原因，影响570万美国人， 但还没有治疗方法。早发性AD最常见的原因是早老素家族性突变， 蛋白酶G-分泌酶的催化亚基。突变的β-分泌酶切割淀粉样前体蛋白（APP）𝛾 并释放与突触丧失相关的毒性β-淀粉样肽。然而，β-分泌酶也可能有助于𝛾 通过APP加工以外的机制来治疗AD中的突触功能障碍。而β-分泌酶有助于𝛾 AD病理学，其在维持人类突触的正常功能方面的更广泛的生理作用很差 明白来自非神经元细胞和小鼠模型的证据表明，β-分泌酶可能过度加工神经元细胞。𝛾 90跨膜蛋白，包括突触信号，支架和粘附蛋白。知识缺口 存在于β-分泌酶如何维持人类神经元中健康突触的正常功能，𝛾 进一步了解AD的病理学。 这项提议的总体目标是研究人类神经元中β-分泌酶如何调节生物化学，𝛾 突触的形态和功能特征，有和没有慢性活动调制。初步 在人类神经元中的工作证实β-分泌酶是β-淀粉样蛋白产生和全长蛋白裂解所必需的。𝛾 APP和Neurexin（Nrxn）蛋白。早期的研究结果表明，β-分泌酶是调节关键酶所必需的。𝛾 突触前和突触后的蛋白质水平，以及突触的数量。 目的1研究β-分泌酶在调节神经元蛋白质组成，突触形成，𝛾 和突触传递，以更好地了解其在人类突触中的功能。我们假设-𝛾 分泌酶是维持突触完整性所必需的，通过突触前和突触后的加工。 proteins.目的2将确定β-分泌酶如何调节突触对慢性增加或𝛾 神经活动减少。由于其他蛋白酶具有活性依赖性调节，我们假设，𝛾 分泌酶在慢性调节后调节突触蛋白组成和突触传递。 了解β-分泌酶在健康突触中的作用，将有助于深入了解生理性突触𝛾 这将促进我们对正常衰老大脑和AD的理解 病理该项目将建立β-分泌酶在人类神经元特异性𝛾 方式进一步揭示β-分泌酶在调节突触活动中的作用.𝛾更深入地了解 人神经元中的蛋白水解活性将阐明AD的候选途径和潜在的治疗靶点。