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）斑块和细胞内神经元tau蛋白缠结（NFT）共同导致 神经炎症、神经变性，以及通常的认知衰退。唐氏综合症（DS）是由于有 三个副本的染色体21（T21）从受孕。Aβ肽是淀粉样蛋白的裂解产物， 前体蛋白（APP），其由APP基因编码。鉴于APP基因位于染色体上 21，所有患有DS的人都在大脑中积累了更高水平的Aβ肽。因此，患有DS的成年人将 发展为AD病理学（DS-AD），并且许多人继续发展为临床痴呆。DS-AD记录了 与典型AD的病理学差异，包括加速的Aβ和tau积累以及更多的 异质性Aβ斑块组成。虽然AD有许多遗传和环境因素 风险，APOE基因，特别是ε4变体（APOE 4），已被确定为最大的风险因素， 典型的AD除了年龄本身。APOE 4的遗传也会显著增加AD和认知能力下降的风险 在DS患者中。在DS患者中进行的队列研究发现， APOE 4，但缺乏对APOE 4在DS患者中的机制作用的研究。显然，有一个 迫切需要研究质疑携带APOE 4的DS患者AD风险增加的机制。 该提案的总体目标是阐明APOE 4基因型在DS-AD发展中的作用 并评估apoE 4驱动Aβ纤维化作为治疗靶点的潜力。具体来说，我将识别APOE 4- 驱动机制和途径，有助于发展DS-AD神经病理学和评估 apoE和/或Aβ的小分子抑制剂在缓解这些病理学方面的功效。完成这些 为了实现这一目标，我将开发新的基于人类诱导多能干细胞（hiPSC）的DS-AD模型， APOE 4.我将从hiPSC中产生多种人类神经细胞类型和脑类器官（CO）， 确定APOE 4在这些发育和衰老的人DS-AD脑模型中的具体作用。我会 评估六种经验证的小分子药物，这些药物已被证明可以预防和/或逆转apoE 4催化的 在我的CO模型系统中的β流化。我的总体假设是，APOE 4将加速并增强 在基于hiPSC的DS-AD模型中AD神经病理学的发展，并且可以用 小分子apoE抑制剂可以缓解这些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.