Roles for activity-dependent microvesicles in neuronal health and disease

阿尔茨海默病(AD)是一种由Aβ定义的衰弱的进行性神经退行性疾病 堆积、tau缠结、突触变化和神经元丢失。AD引发的情感和社会负担 是压倒性的；然而，没有可用的治疗方法。对阿尔茨海默病的致病机制有更深入的了解 迫切需要能够开发有效的治疗方法。细胞外小泡(EVS)是一种高度 释放到细胞外空间的一群不同种类的小膜泡。电动汽车是 与阿尔茨海默病有关，但在神经保护和发病机制中似乎具有相互矛盾的作用。一种可能性是 独特的电动汽车群体已经将角色归因于这种模式，但这一模式尚未得到测试。六跨膜 甘油磷酸二酯磷酸二酯酶2(GDE2或GDPD5)作用于神经元细胞表面，以 切断糖基磷脂酰肌醇(GPI)--将一些蛋白质系在膜上的锚。在成人中 动物，GDE2激活α分泌酶ADAM10，GDE2缺失引发一系列表型 与AD相关的包括Aβ多肽产生增加、突触丢失和神经变性。令人惊讶的是， 阿尔茨海默病患者脑神经元中GDE2的分布和活性受到干扰，但在健康对照组和患者中未见 患有亨廷顿氏症。因此，GDE2功能障碍对AD表现出一定的特异性，并可能与AD有关 发病机制。初步研究表明GDE2是释放微泡(MVS)所必需的，a 直接从质膜发芽的EV亚群，依赖GDE2的MV释放是 神经活动依赖。在GDE2功能丧失的背景下观察到的这些观察结果表明 假设GDE2调节MV亚群的活性依赖性释放，这些亚群是 神经元存活，而这种机制在阿尔茨海默病中的破坏有助于疾病病理。这项建议 我将在三个目标上检验这一假设。目标1将定义GDE2活性依赖的MV释放的机制 在神经元中。AIM 2将检测GDE2释放的MVS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主动支持生存的货物实现的。目标 3将通过对人死后组织的分析来确定GDE2 mV的释放在AD中是否受到干扰。我们的 研究有望为神经元活动驱动提供新的分子和生理学见解 MV的生物发生机制，可能为MVS在AD病理生理中的作用提供新的视角。

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.