Discovering novel players in mechanisms of extracellular vesicle release, cargo loading, and early pathogenesis of late-onset Alzheimer's Disease

阿尔茨海默病（AD）是一种公共卫生危机，随着人口老龄化， 需要对病理生理学有新的见解AD是一种进行性神经退行性疾病， 美国第六大死亡原因，每年给美国带来近5000亿美元的负担。 护理人员和纳税人，预计在未来十年内，患病率将翻一番。的 AD的病理生理学包括通过神经变性和朊病毒样变性引起的突触连接的丧失。 包括β-淀粉样肽（Aβ）的细胞外沉积的蛋白质病的扩散。在散发性AD中， 载脂蛋白E基因（APOE）的变异已成为最大的明显危险因素，AD已 对老年妇女的影响很大。细胞外囊泡（EV），包括外来体，最近出现， 作为AD病理生理学的重要参与者（26-28）。包括多种双叶膜结合 包括我们在内的几个小组已经报道了EV传播与病毒颗粒有关的蛋白质。 在体外和体内的发病机制。某些类型的电动汽车也被建议用于缓解AD 症状，并可作为治疗选择。然而，在这方面仍有许多东西需要学习和利用。 在APOE和性别相关背景下AD和EV的关系。我们计划满足这一需求， 创新的技术和工具。 我们首先假设（目的1-3），神经元和神经元的强大诱导多能干细胞模型， 星形胶质细胞是AD中两种重要的细胞类型，将有助于筛选可能参与AD的因子 通过EV的发病机制。其次（目的2和3），膜运输和膜表面蛋白将 有助于EV释放、与AD相关的货物装载以及对接收者的影响。第三，也是最后一点（目标4）， 在新的类器官和动物模型中调节EV也将调节疾病相关的标志物， 流程.

Alzheimer’s disease (AD) is a public health crisis that continues to grow as the population ages, demanding new insights into pathophysiology. AD, a progressive neurodegenerative disease, is now the sixth-leading cause of death in the United States, places a burden of nearly half a trillion dollars per year on caregivers and taxpayers, and is expected to double in prevalence within the next decade. The pathophysiology of AD includes the loss of synaptic connections through neurodegeneration and the prion-like spread of proteinopathies including extracellular deposition of β-amyloid peptides (Aβ). In sporadic AD, variants of the apolipoprotein E gene (APOE) have emerged as the greatest apparent risk factor, and AD has an outsized effect on aging women. Extracellular vesicles (EVs), including exosomes, have recently emerged as important players in AD pathophysiology (26–28). Comprising a diversity of double-leaflet membrane-bound particles, EVs have been reported by several groups including ours to spread proteins implicated in pathogenesis both in vitro and in vivo. Certain types of EVs have also been suggested to alleviate AD symptoms and may serve as therapeutic options. However, much remains to be learned and exploited in the relationship of AD and EVs in APOE- and gender-associated contexts. We plan to address this need, focusing innovative techniques and tools on the problem. We hypothesize firstly (Aims 1-3) that powerful induced pluripotent stem cell models of neurons and astrocytes, two cell types of central importance in AD, will facilitate screens of factors likely involved in AD pathogenesis via EVs. Secondly (Aims 2 and 3), membrane trafficking and membrane surface proteins will contribute to EV release, AD-related cargo loading, and effects on recipient. Thirdly and finally, (Aim 4), modulating EVs in novel organoid and animal models will also modulate disease-related markers and processes.