Roles for activity-dependent microvesicles in neuronal health and disease

活性依赖性微泡在神经元健康和疾病中的作用

• 批准号: 10426437
• 负责人: SHANTHINI SOCKANATHAN
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426437
• 关键词: Abeta clearance; Abeta synthesis; Address; Age; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Autopsy; Binding; Biochemical; Biogenesis; Biology; Blood - brain barrier anatomy; Brain; Cell membrane; Cell surface; Cells; Cellular Structures; Ceramides; Dementia; Development; Diagnostic; Disease; Distributional Activity; Emotional; Enzymes; Etiology; Excision; Exhibits; Extracellular Space; Failure; Family; Family member; Functional disorder; GPI Membrane Anchors; Health; Human; Huntington Disease; Impairment; Lipids; Mediating; Membrane; Molecular; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Physiological; Plasma; Population; Population Heterogeneity; Production; Prognostic Marker; Property; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Specificity; Structure; Surface; Synapses; Testing; Therapeutic; Tissues; Vertebrates; Vesicle; Viral; abeta accumulation; alpha secretase; base; biophysical properties; cell type; design; effective therapy; exosome; extracellular; extracellular vesicles; glycerophosphodiester phosphodiesterase; insight; intercellular communication; knockout animal; loss of function; mature animal; member; microvesicles; neuron loss; neuronal survival; neuroprotection; neurotoxic; novel; overexpression; particle; phosphoric diester hydrolase; prion-based; role model; synaptic function; tau Proteins; tau aggregation; vesicular release; wasting

Alzheimer's disease (AD) is a debilitating age-progressive neurodegenerative disease defined by Aβ accumulation, tau tangles, synaptic changes, and neuronal loss. Emotional and societal burdens elicited by AD are overwhelming; however, no cures are available. Deeper insight into the mechanisms causal for AD are urgently needed to enable the development of effective therapies. Extracellular vesicles (EVs) are a highly heterogeneous population of small membrane vesicles that are released into the extracellular space. EVs are implicated in AD but appear to have contradictory roles in neuroprotection and pathogenesis. One possibility is that unique populations of EVs have ascribed roles, but this model has not been tested. The six-transmembrane enzyme Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) acts at the cell surface in neurons to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the membrane. In adult animals, GDE2 activates the α-secretase ADAM10 and loss of GDE2 elicits a constellation of phenotypes associated with AD including increased Aβ peptide production, synaptic loss, and neurodegeneration. Strikingly, GDE2 distribution and activity is disrupted in neurons of AD patient brain but not in healthy controls or in patients with Huntington's disease. Thus, GDE2 dysfunction shows some specificity to AD and could contribute to AD pathogenesis. Preliminary studies show that GDE2 is required for the release of microvesicles (MVs), a subpopulation of EVs that bud directly from the plasma membrane, and that GDE2-dependent MV release is neuronal activity-dependent. These observations viewed in context of GDE2 loss of function suggest the hypothesis that GDE2 regulates the activity-dependent release of a subpopulation of MVs that are required for neuronal survival, and that disruption of this mechanism in AD contributes to disease pathology. This proposal will test this hypothesis in three Aims. Aim 1 will define the mechanism of GDE2 activity-dependent MV release in neurons. Aim 2 will examine neuroprotective capabilities of MVs released by GDE2 and distinguish if neuroprotection is achieved through clearance of toxic components or through active pro-survival cargoes. Aim 3 will determine if GDE2 MV release is perturbed in AD through analysis of human postmortem tissues. Our studies are expected to provide new molecular and physiological insight into neuronal activity-driven mechanisms of MV biogenesis and could introduce fresh perspective on roles for MVs in AD pathophysiology.

阿尔茨海默病（AD）是一种由Aβ定义的使人衰弱的年龄进行性神经退行性疾病 在一些实施方案中，所述神经元损伤包括神经元的聚集、tau缠结、突触变化和神经元损失。AD引起的情感和社会负担 是压倒性的;然而，没有治愈方法。更深入地了解AD的因果机制是 迫切需要开发有效的治疗方法。细胞外囊泡（EV）是一种高度 释放到细胞外空间的小膜囊泡的异质群体。用型电动汽车的 与AD有关，但似乎在神经保护和发病机制中具有矛盾的作用。一种可能性是 独特的电动汽车群体具有特定的角色，但这种模型尚未经过测试。六跨膜 甘油磷酸二酯磷酸二酯酶2（GDE 2或GDPD 5）作用于神经元的细胞表面， 切割将一些蛋白质拴在膜上的糖基磷脂酰肌醇（GPI）-锚。成人 在动物中，GDE 2激活α-分泌酶ADAM 10，GDE 2缺失导致一系列表型 与AD相关的疾病包括Aβ肽产生增加、突触丢失和神经变性。引人注目的是， GDE 2分布和活性在AD患者脑的神经元中被破坏，但在健康对照或患者中未被破坏 患有亨廷顿舞蹈症因此，GDE 2功能障碍显示出AD的一些特异性，并可能有助于AD的发生。 发病机制初步研究表明，微泡（MV）的释放需要GDE 2，这是一种 直接从质膜出芽的EV亚群，并且GDE 2依赖性MV释放是 神经元活性依赖性。在GDE 2功能丧失的背景下观察到的这些观察结果表明， 假设GDE 2调节MV亚群的活性依赖性释放，所述MV亚群是 神经元存活，并且AD中这种机制的破坏有助于疾病病理学。这项建议 我们将在三个目标中检验这个假设。目的1将明确GDE 2活性依赖性MV释放的机制 在神经元中。目的2将检查GDE 2释放的MV的神经保护能力，并区分 神经保护是通过清除有毒成分或通过活性促存活物质来实现的。目的 3将通过分析人死后组织来确定AD中GDE 2 MV释放是否受到干扰。我们 这些研究有望为神经元活动驱动的 MV的生物发生机制，并可能引入新的观点的作用，MV在AD的病理生理学。