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: 10388131
• 负责人: Jeffrey Nicholas Savas
• 金额: $ 44.69万
• 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/10388131
• 关键词: AMPA Receptors; Acute; Address; Affect; Age; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Biochemical; Biogenesis; Bioinformatics; Brain; 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; Lentivirus; 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; 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.

抽象的 突触功能障碍代表了阿尔茨海默氏病（AD）的核心病理标志。障碍 突触是神经元电路活性的变化的基础，这些变化最终导致AD中的认知受损。 尽管如此，我们目前对AD中的突触如何以及为什么更改的方式有不完整的了解 病理。如果我们能够提高对引起突触功能障碍的基本机制的理解 在AD中，这将是对AD的整体理解的重大进步。最近的证据表明 这种致病性淀粉样蛋白β和TAU富含细胞外囊泡和外泌体。但是这些囊泡如何 尚不清楚促进疾病进展，特别是它们如何影响突触功能。在初步 研究，我们提供的证据表明，突触NMDA受体的激活触发神经元中外泌体释放， 并且这个过程调节了许多突触蛋白的水平。重要的是，对这些复杂的分析 使用多种生物信息学策略的数据集突出显示了关键的蛋白质 - 蛋白质相互作用网络 受外泌体调节，包括AMPA受体的存在，淀粉样蛋白前体蛋白（APP）和Tau。 来自刺激神经元的纯化外泌体的蛋白质组学分析揭示了几种蛋白质的存在 已知会导致神经变性，这表明此过程可能在扩散中具有重要作用 病理。 WT神经元中外泌体合成的抑制消除了突触增强 以前未知的外泌体信号传导功能。分析来自多个大脑的纯化外泌体 具有广告状病理学的小鼠模型表明，应用程序和淀粉样β肽的富集以及 外泌体蛋白兑换的改变。基于此证据，我们假设正常的外泌体信号传导 被广告病理学劫持，导致突触功能障碍已知在该疾病中普遍存在。我们 提出活动诱导的外泌体通常支持突触增强，被 病原分子的异常富集，尤其会导致突触破坏 突触增强。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，非偏置蛋白质组学方法和 外部释放动力学的成像。拟议的研究有可能改变我们的理解 关于活性诱导的外泌体信号传导的改变可能导致突触功能障碍和AD-的扩散 喜欢病理。

项目成果

Biochemical Purification and Proteomic Characterization of Amyloid Fibril Cores from the Brain.

• DOI: 10.3791/63816
• 发表时间: 2022-04-28
• 期刊: Journal of visualized experiments : JoVE
• 作者: Upadhyay A;Vassar RJ;Savas JN
• 通讯作者: Savas JN

Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer.

• DOI: 10.1038/s41467-020-18956-x
• 发表时间: 2020-10-14
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Apóstolo N;Smukowski SN;Vanderlinden J;Condomitti G;Rybakin V;Ten Bos J;Trobiani L;Portegies S;Vennekens KM;Gounko NV;Comoletti D;Wierda KD;Savas JN;de Wit J
• 通讯作者: de Wit J

The Dichotomous Role of Extracellular Vesicles in the Central Nervous System.

• DOI: 10.1016/j.isci.2020.101456
• 发表时间: 2020-09-25
• 期刊: iScience
• 影响因子: 5.8
• 作者: Graykowski, David R;Wang, Yi-Zhi;Savas, Jeffrey N
• 通讯作者: Savas, Jeffrey N