The role of activity induced exosome signaling in synaptic pathology of Alzheimer's Disease

活性诱导的外泌体信号在阿尔茨海默病突触病理学中的作用

• 批准号: 9788258
• 负责人: Jeffrey Nicholas Savas
• 金额: $ 48万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9788258
• 关键词: AMPA Receptors; Acute; Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biochemical; Biogenesis; Bioinformatics; Brain; Brain Diseases; Cell physiology; Cells; Chemosensitization; Communication; Complex; Data Set; Dementia; Discipline; Disease; Disease Progression; Electron Microscopy; Electrophysiology (science); Foundations; Functional disorder; Goals; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; In Vitro; Knock-in; Knock-in Mouse; Label; Long-Term Potentiation; Mass Spectrum Analysis; Measurement; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Physiological; Play; Process; Property; Protein Fragment; Proteins; Proteome; Proteomics; Research; Role; Signal Transduction; Slice; Subfamily lentivirinae; Synapses; Synaptic plasticity; Techniques; Testing; Time; Toxic effect; Vesicle; Western Blotting; amyloid precursor protein processing; base; brain tissue; comparative; design; exosome; experimental study; extracellular vesicles; in vivo; infancy; knock-down; live cell imaging; mouse model; mutant; neuronal circuitry; neurotransmission; patch clamp; protein protein interaction; response; small hairpin RNA; synaptic function; tau Proteins; tau-1

ABSTRACT Synaptic dysfunction represents a core pathological hallmark of Alzheimer's disease (AD). Impairments in synapses underlie changes in the activity of neuronal circuits, which ultimately drive impaired cognition in AD. Despite this, we currently have an incomplete understanding of how and why synapses are altered in AD pathology. If we could advance our understanding of the underlying mechanisms that cause synaptic dysfunction in AD, it would be a significant advancement in the overall understanding of AD. Recent evidence has suggested that pathogenic amyloid beta and tau are enriched in extracellular vesicles and exosomes; but how these vesicles contribute to disease progression, particularly how they affect synaptic function, is still unknown. In preliminary studies, we provide evidence that activation of synaptic NMDA receptors triggers exosome release in neurons, and that this process regulates the level of many synaptic proteins. Importantly, an analysis of these complex datasets using multiple bioinformatic strategies, highlighted key protein-protein interaction networks that are regulated by exosomes including the presence of AMPA receptors, amyloid precursor protein (APP), and tau. Proteomic analysis of purified exosomes from stimulated neurons revealed the presence of several proteins known to cause neurodegeneration, and it suggests that this process may have a major role in the spreading of pathology. Inhibition of exosome synthesis in WT neurons eliminated synaptic potentiation demonstrating a previously unknown function of exosome signaling. Analysis of purified exosomes from the brains of multiple mouse models with AD-like pathology demonstrated an enrichment of APP and amyloid beta peptide as well as an alteration of exosome protein cargos. Based on this evidence, we hypothesize that normal exosome signaling is hijacked by AD pathology contributing to the synaptic dysfunction known to be prevalent in the disease. We propose that activity-induced exosomes, which normally support synaptic strengthening, are overwhelmed by aberrant enrichment of pathogenic molecules which results in disrupted synapses, in particular, impaired synaptic strengthening. We plan to test this hypothesis by combining orthogonal techniques and disciplines including electrophysiological measurement of synaptic function, non-biased proteomic approaches, and imaging of exosome release dynamics. The proposed research has the potential to transform our understanding of how altered activity-induced exosome signaling may contribute to synaptic dysfunction and spreading of AD- like pathology.

摘要 突触功能障碍是阿尔茨海默病(AD)的一个核心病理特征。减值 突触是神经元回路活动变化的基础，最终导致AD患者认知功能受损。 尽管如此，我们目前对AD中突触改变的方式和原因仍有不完全的了解 病理学。如果我们能进一步了解导致突触功能障碍的潜在机制 在AD中，这将是对AD整体理解的一个重大进步。最近的证据表明 致病的淀粉样蛋白β和tau在细胞外泡和外切体中富含；但这些囊泡是如何 对疾病进展的贡献，特别是它们如何影响突触功能，目前仍不清楚。在预赛中 研究表明，突触NMDA受体的激活会触发神经元中外切体的释放， 这个过程调节着许多突触蛋白的水平。重要的是，对这些情结的分析 使用多种生物信息学策略的数据集，强调了关键的蛋白质-蛋白质相互作用网络 受外体调节，包括AMPA受体、淀粉样前体蛋白(APP)和tau的存在。 从刺激神经元中提纯的外切体的蛋白质组学分析显示存在几种蛋白质 已知会导致神经退变，这表明这一过程可能在霍乱的传播中起着重要作用 病理学。抑制WT神经元外体合成消除了突触增强作用 先前未知的外体信号功能。多发性脑脊髓炎患者脑组织中纯化的外切体分析 AD样病理的小鼠模型显示APP和淀粉样β蛋白以及 外切体蛋白货物的变化。基于这一证据，我们假设正常的外切体信号 被AD病理劫持，导致已知在该疾病中普遍存在的突触功能障碍。我们 认为正常情况下支持突触加强的活动诱导的外体被 致病分子异常浓缩，导致突触破坏，尤其是受损 突触加强。我们计划通过结合正交技术和学科来检验这一假设。 包括突触功能的电生理测量，无偏倚蛋白质组学方法，以及 外切体释放动力学的成像。这项拟议的研究有可能改变我们对 活性改变诱导的外切体信号如何可能有助于突触功能障碍和AD的传播- 就像病理学。