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)是一种随着人口老龄化而持续增长的公共健康危机， 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，现在是 美国第六大死因，每年给美国带来近5000亿美元的负担 这一群体主要是照料者和纳税人，预计在未来十年内患病率将翻一番。这个 阿尔茨海默病的病理生理学包括通过神经退行性变和蛋白样蛋白丢失突触连接 蛋白质病的扩散，包括β-淀粉样多肽(Aβ)的细胞外沉积。在零星的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，而AD 对老年女性的影响太大了。细胞外小泡(EV)，包括外体，最近已经出现 作为AD病理生理学的重要参与者(26-28)。包括多样性的双小叶膜结合 颗粒，EVS已经被包括我们在内的几个小组报告了传播与 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来缓解AD 症状，并可作为治疗选择。然而，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EVS的关系。我们计划满足这一需求，重点是 解决这一问题的创新技术和工具。 我们首先假设(目标1-3)强大的诱导多能干细胞模型的神经元和 星形胶质细胞是阿尔茨海默病中两种重要的细胞类型，将有助于筛选可能与阿尔茨海默病有关的因素 通过EVS的发病机制。其次(目标2和3)，膜转运和膜表面蛋白 有助于电动汽车的释放，AD相关货物的装载，以及对接受者的影响。第三也是最后一点，(目标4)， 在新的器官和动物模型中调节EV也将调节疾病相关标记物和 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.