Investigating and targeting apolipoprotein E4 in Down syndrome-associated Alzheimer's disease

项目总结摘要 到40岁时，每个患有唐氏综合症的人都会有阿尔茨海默病的脑部病理，而且大多数人都会 由于淀粉样前体蛋白基因(APP)的三倍增加，继续发展为阿尔茨海默病痴呆 它位于21号染色体上。作为最强的遗传风险因素和最大的总体风险因素 在典型的阿尔茨海默病人群中，除了年龄本身的增加外，ε4等位基因的遗传 载脂蛋白E基因(APOE)也显著增加了人们患阿尔茨海默病的风险和严重程度 患有唐氏综合症。我们发现了载脂蛋白E促进阿尔茨海默病的一个关键机制：它结合 Aβ肽，并将其转化为一种有毒物种，可杀死神经元并导致神经退化，与 ApoE4形式是最有效的淀粉样蛋白催化剂。鉴于载脂蛋白E对 阿尔茨海默病，关键是阿尔茨海默病风险增加的潜在机制 阐明唐氏综合症患者，并开发新的治疗方法，以有效地针对其 致病活性。我们已经开发了一种体外试验来筛选NIH临床收藏(NCC)小分子 载脂蛋白E4催化的Aβ寡聚体/纤维形成抑制剂的分子库。我们已经确认了八次命中 化合物，其中每一种都曾在I-III期临床试验中测试过其他适应症，因此 有已知的安全配置文件。在二次筛选中，我们发现8个初始化合物中有3个是 ApoE的非神经毒性抑制剂可显著降低A-β和Tau的病理和细胞死亡 阿尔茨海默病的两种啮齿动物模型。此外，国家阿尔茨海默氏症协调中心的分析 中心(NACC)的数据库显示，我们发现阿尔茨海默病患者使用了两种载脂蛋白E抑制剂中的任何一种 随着时间的推移，患者的认知能力会得到改善，恢复到更好的临床状态的几率也会增加。 诊断从阿尔茨海默病到轻度认知障碍(MCI)或从MCI到正常认知，提供 为他们的进一步学习提供翻译支持。在这里，我们将使用一组人类诱导的多能干细胞 (IPSC)衍生的唐氏综合征和阿尔茨海默病的脑器官(CO)模型研究 载脂蛋白E诱导阿尔茨海默病表型的机制以及评估我们的首选候选载脂蛋白E 抑制剂可以阻止唐氏综合征患者阿尔茨海默病表型的发展。我们还将发展 第一个表达人载脂蛋白4的唐氏综合征小鼠模型的建立及对我们的最佳候选者能力的评估 APOE抑制剂可预防认知障碍、脑血管损伤、突触功能障碍， 唐氏综合征相关阿尔茨海默病新模型中的神经变性和/或神经炎症 疾病，以便为未来的临床试验提供信息。我们建议的方法应该会导致高度靶向性的阿尔茨海默氏症 唐氏综合症患者的疾病治疗几乎没有副作用，因为抑制 载脂蛋白E4和Aβ的相互作用不应该或可以选择不影响载脂蛋白E的正常功能。

PROJECT SUMMARY ABSTRACT By the age of forty, every person with Down syndrome has Alzheimer's disease brain pathology, and most will go on to develop Alzheimer's disease dementia, due to triplication of the amyloid precursor protein gene (APP) that resides on chromosome 21. As the strongest genetic risk factor and greatest overall risk factor for Alzheimer's disease in the typical population, other than increasing age itself, inheritance of the ε4 allele of the apolipoprotein E gene (APOE) also significantly increases the risk and severity of Alzheimer's disease in people with Down syndrome. We have found a key mechanism by which apoE promotes Alzheimer's disease: it binds to the Aβ peptide and converts it into a toxic species that kills neurons and causes neurodegeneration, with the apoE4 form being the most effective amyloid catalyst. In view of the essential contributions of apoE to Alzheimer's disease, it is critical that the mechanisms underlying the enhanced Alzheimer's disease risk for people with Down syndrome be elucidated and that new therapies be developed to effectively target its pathogenic activity. We have developed an in vitro assay to screen the NIH Clinical Collection (NCC) small molecule library for inhibitors of apoE4-catalyzed Aβ oligomer/fibril formation. We have identified eight hit compounds, each of which has been tested previously in Phase I-III clinical trials for other indications and thus have known safety profiles. In a secondary screen, we found that three out of the eight initial compounds were non-neurotoxic inhibitors of apoE that significantly reduced Aβ and tau pathology and cell death in neurons from two rodent models of Alzheimer's disease. Furthermore, an analysis of the National Alzheimer's Coordinating Center (NACC) database showed use of either one of two drugs we identified as apoE inhibitors by Alzheimer's patients was associated with improved cognition over time and increased odds of reverting to a better clinical diagnosis from Alzheimer's disease to mild cognitive impairment (MCI) or from MCI to normal cognition, providing translational support for their further study. Herein, we will use a panel of human induced pluripotent stem cell (iPSC)-derived cerebral organoid (CO) models of Down syndrome and Alzheimer's disease to study the mechanisms of apoE-induced Alzheimer's disease phenotypes and to evaluate whether our top candidate apoE inhibitors can block the development of Alzheimer's disease phenotypes in Down syndrome. We will also develop the first mouse model of Down syndrome expressing human APOE4 and assess the ability of our top candidate apoE inhibitors to prevent the development of cognitive deficits, cerebrovascular damage, synaptic dysfunction, neurodegeneration, and/or neuroinflammation in this novel model of Down syndrome-associated Alzheimer's disease in order to inform future clinical trials. Our proposed approach should result in highly targeted Alzheimer's disease therapies for people with Down syndrome with few side effects, because the drugs that inhibit the interaction of apoE4 and Aβ should not, or can be selected to not, affect the normal functions of apoE.