Individual Predoctoral Fellowship

个人博士前奖学金

• 批准号: 10752036
• 负责人: Breanna Dooling
• 金额: $ 3.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-02 至 2027-02-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752036
• 关键词: Acceleration; Adult; Age; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Apolipoproteins; Astrocytes; Biological Models; Brain; Brain Pathology; Cerebrum; Chromosome 21; Clinical; Clinical Trials; Cohort Studies; Communities; Conceptions; Dementia; Development; Down Syndrome; Effectiveness; Environmental Risk Factor; Fellowship; Future; Gene Proteins; Genes; Genetic; Genotype; Goals; Human; Impaired cognition; Individual; Investigation; Measures; Mediating; Microglia; Modeling; Morphology; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Observational Study; Organoids; Pathologic; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Polymers; Population; Prosencephalon; Proteins; Publishing; Quality of life; Relative Risks; Research; Risk; Risk Factors; Risk Reduction; Role; Senile Plaques; Severities; Severity of illness; Testing; Therapeutic; Treatment Efficacy; Variant; apolipoprotein E-3; apolipoprotein E-4; brain cell; cell type; cohort; disease phenotype; drug candidate; effective therapy; efficacy evaluation; experimental study; extracellular; familial Alzheimer disease; genetic variant; improved; induced pluripotent stem cell; inhibitor; neurodegenerative phenotype; neuroinflammation; neuropathology; novel; novel therapeutic intervention; novel therapeutics; polymerization; pre-doctoral; prevent; small molecular inhibitor; small molecule; small molecule inhibitor; stem cell model; tau aggregation; tau-1; therapeutic target; tool

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.

抽象的 阿尔茨海默病是一种神经退行性疾病，其特征是细胞外淀粉样蛋白的积累 β (Aβ) 斑块和细胞内神经原纤维 tau 缠结 (NFT) 共同促进 神经炎症、神经退行性变以及通常的认知能力下降都是患有唐氏综合症的结果。 受孕时 21 号染色体 (T21) 的三个拷贝 Aβ 肽是淀粉样蛋白的裂解产物。 前体蛋白（APP），由 APP 基因编码，因为 APP 基因位于染色体上。 21、所有 DS 患者的大脑中 Aβ 肽的积累水平都较高，因此，患有 DS 的成年人也会积聚较高水平的 Aβ 肽。 发展 AD 病理学（DS-AD），并且许多人继续发展临床 DS-AD 已被记录。 与典型 AD 的病理差异，包括加速 Aβ 和 tau 积累以及更多 AD 的遗传和环境因素有很多。 APOE 基因，尤其是 ε4 变体 (APOE4)，已被确定为最大的风险因素 除了 APOE4 遗传之外，典型的 AD 年龄也会显着增加 AD 和认知能力下降的风险。 对 DS 患者的队列研究发现，AD 风险总体增加。 APOE4，但缺乏对 APOE4 在 DS 患者中的机制作用的研究，显然，存在这种机制。 迫切需要研究探究携带 APOE4 的 DS 患者患 AD 风险增加的机制。 该提案的总体目标是阐明 APOE4 基因型在 DS-AD 发展中的作用 并评估 apoE4 驱动 Aβ 纤维化作为治疗靶点的潜力。具体来说，我将确定 APOE4-。 有助于 DS-AD 神经病理学发展的驱动机制和途径并评估 apoE 和/或 Aβ 小分子抑制剂在缓解这些病理方面的功效。 为了实现这一目标，我将开发新型基于人类诱导多能干细胞 (hiPSC) 的 DS-AD 模型，该模型携带 APOE4。我将从 hiPSC 中生成多种人类神经细胞类型和大脑类器官 (CO)。 我将确定 APOE4 在这些发育和衰老的人类 DS-AD 大脑模型中的具体作用。 评估六种经过验证的小分子药物，这些药物已被证明可以预防和/或逆转 apoE4 催化的疾病 我的 CO 模型系统中的 Aβ 纤维化我的总体假设是 APOE4 会加速和增强。 AD 神经病理学在基于 hiPSC 的 DS-AD 模型中的发展，并且可以针对 小分子 apoE 抑制剂可缓解这些 AD 表型。