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

研究和靶向唐氏综合症相关阿尔茨海默病中的载脂蛋白 E4

• 批准号: 10658660
• 负责人: Noah Ray Johnson
• 金额: $ 228.25万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658660
• 关键词: Adverse effects; Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Binding; Biological Markers; Blood; Brain; Brain Pathology; Cell Death; Cells; Cerebrum; Chromosome 21; Clinical; Clinical Trials; Cognition; Cognitive deficits; Collection; Communities; Cross Syndrome; Data Coordinating Center; Data Set; Databases; Dementia; Deposition; Development; Disease; Down Syndrome; Electrophysiology (science); FDA approved; Functional disorder; Future; Gene Expression Profile; Gene Proteins; Genes; Health; Hemorrhage; Human; Imipramine; Immunohistochemistry; Immunotherapy; Impaired cognition; Inflammatory; Knock-in Mouse; Libraries; Mediating; Modeling; Molecular; Mus; Nerve Degeneration; Neuroglia; Neuronal Dysfunction; Neurons; Organoids; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Phase; Phenotype; Polymers; Population; Pre-Clinical Model; Proteins; Research; Risk; Rodent Model; Safety; Seminal; Senile Plaques; Series; Severities; Synapses; Testing; Therapeutic; Time; Transgenic Mice; United States National Institutes of Health; Vertebral column; Western Blotting; abeta oligomer; amyloid formation; apolipoprotein E-4; behavior test; blood-brain barrier permeabilization; catalyst; cerebrovascular; clinical diagnosis; density; design; disease phenotype; drug candidate; efficacy evaluation; experimental study; genetic risk factor; high risk; high throughput screening; improved; in vitro Assay; in vivo Model; induced pluripotent stem cell; inhibitor; innovation; mild cognitive impairment; mouse model; neuroinflammation; neuropathology; neurotoxic; novel; novel therapeutics; olanzapine; polymerization; preclinical efficacy; preclinical evaluation; prevent; prospective; side effect; small molecule; small molecule libraries; tau Proteins; tool; transcriptomics

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.

项目摘要 到四十岁时，每个唐氏综合症患者都有阿尔茨海默病的大脑病理，大多数人会 由于淀粉样前体蛋白基因（APP）的三倍化， 位于21号染色体上作为最强的遗传风险因素和最大的整体风险因素， 阿尔茨海默病在典型人群中，除了年龄本身的增加外， 载脂蛋白E基因（APOE）也会显著增加老年痴呆症的风险和严重程度 患有唐氏综合症我们已经发现了apoE促进阿尔茨海默病的一个关键机制： Aβ肽并将其转化为一种有毒物质，杀死神经元并导致神经变性， apoE 4形式是最有效的淀粉样蛋白催化剂。考虑到apoE对 阿尔茨海默氏病，这是至关重要的机制，增强阿尔茨海默氏病的风险， 阐明唐氏综合症患者的病情，并开发新的疗法来有效地针对其 致病活性我们已经开发了一种体外试验来筛选NIH临床收集（NCC）小 ApoE 4催化的Aβ寡聚体/原纤维形成抑制剂的分子库。我们已经确认了八名 这些化合物中的每一种先前已经在I-III期临床试验中针对其他适应症进行了测试，因此 都有已知的安全性在二次筛选中，我们发现八种初始化合物中有三种是 apoE的非神经毒性抑制剂，可显著减少Aβ和tau病理学以及神经元中的细胞死亡， 两个老年痴呆症的啮齿动物模型。此外，对全国阿尔茨海默氏症协调中心的分析表明， NACC数据库显示，阿尔茨海默病患者使用我们确定为apoE抑制剂的两种药物之一， 随着时间的推移，患者的认知能力得到改善，恢复到更好的临床状态的几率增加。 从阿尔茨海默病到轻度认知障碍（MCI）或从MCI到正常认知的诊断， 翻译支持他们的进一步研究。在此，我们将使用一组人类诱导多能干细胞， （iPSC）衍生的唐氏综合征和阿尔茨海默病的脑类器官（CO）模型，以研究 apoe诱导阿尔茨海默病表型的机制并评估我们的首选apoE是否 抑制剂可以阻断唐氏综合征中阿尔茨海默病表型的发展。我们还将开发 第一个表达人APOE 4的唐氏综合征小鼠模型，并评估我们的首选候选人的能力， apoE抑制剂预防认知缺陷、脑血管损伤、突触功能障碍的发展， 神经退行性变和/或神经炎症在这个新的唐氏综合征相关的阿尔茨海默病模型中的作用 疾病，以便为未来的临床试验提供信息。我们提出的方法应该会导致高度针对性的阿尔茨海默氏症 唐氏综合症患者的疾病疗法几乎没有副作用，因为抑制 apoE 4和Aβ的相互作用不应该或可以选择不影响apoE的正常功能。