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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer&apos 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

项目摘要

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.

项目概要摘要到了四十岁，每个患有唐氏综合症的人都会患有阿尔茨海默病脑部病变，而且大多数人都会出现这种情况由于淀粉样前体蛋白基因 (APP) 的三重复制，继续发展为阿尔茨海默病痴呆位于 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典型人群中的阿尔茨海默病，除了年龄本身的增加之外，还与 ε4 等位基因的遗传有关。载脂蛋白 E 基因 (APOE) 也会显着增加人们患阿尔茨海默病的风险和严重程度我们发现了 apoE 促进阿尔茨海默病的一个关键机制：它与唐氏综合症患者结合。 Aβ肽并将其转化为有毒物质，杀死神经元并导致神经退行性变鉴于 apoE 对淀粉样蛋白的重要贡献，apoE4 形式是最有效的淀粉样蛋白催化剂。阿尔茨海默病，至关重要的是，了解阿尔茨海默病风险增加的潜在机制阐明患有唐氏综合症的人，并开发新的疗法来有效地针对其我们开发了一种体外检测方法来筛选 NIH 临床收藏品 (NCC) 小样本。 apoE4 催化 Aβ 寡聚体/原纤维形成抑制剂的分子库我们已鉴定出八个命中目标。每种化合物之前都已在 I-III 期临床试验中针对其他适应症进行了测试，因此在二次筛选中，我们发现八种初始化合物中的三种是已知的安全性。 apoE 的非神经毒性抑制剂，可显着减少神经元中的 Aβ 和 tau 病理学以及细胞死亡两种阿尔茨海默病的啮齿动物模型此外，还对国家阿尔茨海默病协调中心进行了分析。中心 (NACC) 数据库显示，阿尔茨海默病患者使用了我们确定为 apoE 抑制剂的两种药物中的任何一种随着时间的推移，患者的认知能力得到改善，并且恢复到更好的临床状态的几率增加。从阿尔茨海默病诊断为轻度认知障碍 (MCI) 或从 MCI 诊断为正常认知，提供在此，我们将使用一组人类诱导多能干细胞为他们的进一步研究提供翻译支持。 (iPSC) 衍生的唐氏综合症和阿尔茨海默病的脑类器官 (CO) 模型，用于研究 apoE 诱导阿尔茨海默氏病表型的机制，并评估我们的最佳候选 apoE 是否我们还将开发抑制剂可以阻止唐氏综合症中阿尔茨海默病表型的发展。第一个表达人类 APOE4 的 Down 小鼠模型并评估我们最佳候选者的能力 apoE 抑制剂可预防认知缺陷、脑血管损伤、突触功能障碍、这种唐氏综合症相关阿尔茨海默病的新模型中的神经退行性变和/或神经炎症以便为未来的临床试验提供信息，我们提出的方法应该能够产生高度针对性的阿尔茨海默病。唐氏综合症患者的疾病治疗几乎没有副作用，因为抑制唐氏综合症的药物 apoE4 和 Aβ 的相互作用不应或可以选择不影响 apoE 的正常功能。