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.

项目摘要摘要到40岁时，每个患有唐氏综合症的人都患有阿尔茨海默氏病脑病理学，大多数人都会由于淀粉样蛋白前体蛋白基因（APP）的一式字母，继续发展阿尔茨海默氏病痴呆症这是在21号染色体上的典型人群中的阿尔茨海默氏病，除了增加年龄本身以外，ε4等位基因的遗传载脂蛋白E基因（APOE）也显着增加了人们对人类疾病的风险和严重程度唐氏综合症。我们发现了APOE促进阿尔茨海默氏病的关键机制：它结合了到Aβ果皮并将其转化为杀死神经元并引起神经变性的有毒物种 APOE4形式是最有效的淀粉样蛋白催化剂。鉴于Apoe对阿尔茨海默氏病，至关重要阐明患有唐氏综合症的人，并开发出新的疗法以有效地针对致病活性。我们已经开发了一项体外评估，以筛选NIH临床收集（NCC）小分子库，用于APOE4催化的Aβ低聚物/原纤维形成的抑制剂。我们已经确定了八次命中化合物，每种化合物先前已在I-III期临床试验中进行了其他适应症，因此具有已知的安全概况。在次要屏幕中，我们发现八个初始化合物中有三个是 APOE的非神经毒性抑制剂显着降低了来自Aβ的Aβ和TAU病理学和细胞死亡的神经元中的神经元死亡阿尔茨海默氏病的两个啮齿动物模型。此外，对国家阿尔茨海默氏症协调的分析中心（NACC）数据库显示了我们通过阿尔茨海默氏症鉴定为APOE抑制剂的两种药物之一随着时间的流逝，患者的认知能力得到改善，并增加了恢复到更好的临床的几率从阿尔茨海默氏病到轻度认知障碍（MCI）或从MCI到正常认知的诊断，提供对他们进一步研究的翻译支持。在此，我们将使用一组人类诱导的多能干细胞（IPSC）唐氏综合症和阿尔茨海默氏病的衍生脑器官（CO）模型 APOE诱导的阿尔茨海默氏病表型的机制，并评估我们的顶级候选APOE是否是抑制剂可以阻止唐氏综合症中阿尔茨海默氏病表型的发展。我们还将发展表达人APOE4的唐氏综合症的第一个小鼠模型并评估我们的顶级候选人的能力 APOE抑制剂可防止认知缺陷的发展，脑血管损伤，突触功能障碍，在唐氏综合症相关的阿尔茨海默氏症的新型模型中，神经变性和/或神经炎症疾病以告知未来的临床试验。我们提出的方法应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，因为抑制这种药物的药物 APOE4和Aβ的相互作用不应或不应选择不影响APOE的正常功能。