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) 是一种使人衰弱的年龄进行性神经退行性疾病，由 Aβ 定义 AD 引起的情绪和社会负担。 是势不可挡的；然而，目前还没有更深入的了解AD的病因机制。 细胞外囊泡（EV）是开发有效疗法的迫切需要。 释放到细胞外空间的小膜囊泡的异质群体是。 与 AD 有关，但在神经保护和发病机制中似乎具有矛盾的作用。 一种可能性是。 独特的电动汽车群体具有指定的角色，但该模型尚未经过测试。 甘油磷酸二酯磷酸二酯酶 2（GDE2 或 GDPD5）作用于神经元的细胞表面， 裂解成人体内将某些蛋白质束缚在膜上的糖基磷脂酰肌醇 (GPI) 锚。 在动物中，GDE2 激活 α-分泌酶 ADAM10，GDE2 的缺失会引发一系列表型 与 AD 相关的因素包括 Aβ 肽产生增加、突触损失和神经变性。 AD 患者大脑神经元中的 GDE2 分布和活性受到破坏，但健康对照或患者中并未出现这种情况 因此，GDE2 功能障碍对 AD 具有一定的特异性，并可能导致 AD。 初步研究表明，GDE2 是微泡 (MV) 释放所必需的，微泡是一种微泡。 直接从质膜出芽的 EV 亚群，并且 GDE2 依赖性 MV 释放是 这些观察结果表明 GDE2 功能丧失 假设 GDE2 调节 MV 亚群的活动依赖性释放，这些亚群是 神经元存活，并且 AD 中这种机制的破坏有助于疾病病理学。 将在三个目标中检验这一假设。目标 1 将定义 GDE2 活性依赖性 MV 释放的机制。 目标 2 将检查 GDE2 释放的 MV 的神经保护能力并区分是否 神经保护是通过清除有毒成分或通过活性的促生存货物来实现的。 3 将通过对人类死后组织的分析来确定 GDE2 MV 释放在 AD 中是否受到干扰。 研究预计将为神经活动驱动提供新的分子和生理学见解 MV 生物发生机制，并可为 MV 在 AD 病理生理学中的作用引入新的视角。