Individual Predoctoral Fellowship

摘要 阿尔茨海默病是一种以细胞外淀粉样蛋白积聚为特征的神经退行性疾病 β(Aβ)斑块和细胞内神经原纤维tau缠结(NFT)共同作用于 神经炎症、神经退行性变，通常还有认知能力下降。唐氏综合症(DS)是由于 来自受孕的21号染色体(T21)的三个副本。Aβ肽是淀粉样蛋白的裂解产物 前体蛋白(APP)，由APP基因编码。鉴于APP基因位于染色体上 21，所有患有DS的人在他们的大脑中积累了更高水平的Aβ肽。因此，患有DS的成年人将 发展AD病理学(DS-AD)，许多人继续发展为临床痴呆症。DS-AD已记录 与典型AD的病理差异包括加速的Aβ和tau蓄积以及更多 异质性A-β斑块组成。虽然有许多遗传和环境因素导致阿尔茨海默病 风险，载脂蛋白E基因，特别是ε4变异(载脂蛋白4)已被确定为最大的风险因素 除了年龄本身，还有典型的AD。APOE4基因的遗传也显著增加了阿尔茨海默病和认知能力下降的风险 在患有DS的个体中。对DS患者进行的队列研究发现，以下因素导致AD风险总体增加 载脂蛋白E4，但缺乏对载脂蛋白E4在DS患者中的机制作用的研究。显然，有一个 迫切需要对携带APOE4的DS患者AD风险增加的机制进行研究。 这项建议的总体目标是阐明APOE4基因在DS-AD发病中的作用 并评估载脂蛋白E4驱动的Aβ纤化作为治疗靶点的潜力。具体地说，我将确定APOE4- 促进DS-AD神经病理发展和评估的驱动机制和途径 载脂蛋白E和/或A-β的小分子抑制剂在减轻这些病变方面的疗效。要实现这些目标 目标，我将开发基于人类诱导多能干细胞(HiPSC)的DS-AD新模型，该模型携带 载脂蛋白E4.我将从HiPSCs中产生多种人类神经细胞类型和脑器官(Cos) 确定APOE4在这些发育和老化的人类DS-AD脑模型中的具体作用。这就做 评估六种已被证明可以预防和/或逆转apoE4催化的有效小分子药物 我的CO模型系统中的βFILENIZED。我的总体假设是，APOE4将加速并增强 基于HiPSC的DS-AD模型中阿尔茨海默病神经病理学的发展 小分子载脂蛋白E抑制剂，以减轻这些AD表型。

ABSTRACT Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tau tangles (NFTs) which together contribute to neuroinflammation, neurodegeneration, and often cognitive decline. Down syndrome (DS) is the result of having three copies of chromosome 21 (T21) from conception. The Aβ peptide is a cleavage product of the amyloid precursor protein (APP) which is encoded by the APP gene. Given that the APP gene resides on chromosome 21, all people with DS accumulate higher levels of Aβ peptide in their brains. Accordingly, adults with DS will develop AD pathology (DS-AD), and many go on to develop clinical dementia. DS-AD has documented pathological differences from typical AD, including accelerated Aβ and tau accumulation and a more heterogeneous Aβ plaque composition. While there are numerous genetic and environmental contributors to AD risk, the APOE gene, and especially the ε4 variant (APOE4), has been identified as the greatest risk factor for typical AD besides age itself. Inheritance of APOE4 also significantly increases risk for AD and cognitive decline in individuals with DS. Cohort studies in people with DS have found an overall increased AD risk conferred by APOE4, but investigations of the mechanistic role of APOE4 in people with DS are lacking. Clearly, there is an urgent need for studies interrogating the mechanism of increased risk of AD for people with DS carrying APOE4. The overall goal of this proposal is to elucidate the role of the APOE4 genotype in the development of DS-AD and assess the potential of apoE4-drive Aβ fibrilization as a therapeutic target. Specifically, I will identify APOE4- driven mechanisms and pathways that contribute to the development of DS-AD neuropathologies and assess the efficacy of small molecular inhibitors of apoE and/or Aβ in alleviating these pathologies. To accomplish these goals, I will develop novel human induced pluripotent stem cell (hiPSC)-based models of DS-AD that carry APOE4. I will generate multiple human neural cell types and cerebral organoids (COs) from the hiPSCs to determine the specific effects of APOE4 in these models of the developing and aging human DS-AD brain. I will evaluate six validated small molecule drugs that have been shown to prevent and/or reverse apoE4-catalyzed Aβ fibrillization in my CO model system. My overall hypothesis is that APOE4 will accelerate and enhance the development of AD neuropathologies in hiPSC-based models of DS-AD and can be targeted with small molecule apoE inhibitors to alleviate those AD phenotypes.