Effects of ApoE-enhancing Compounds on Alzheimers Disease Phenotypes In Vivo

ApoE 增强化合物对体内阿尔茨海默病表型的影响

• 批准号: 9752688
• 负责人: John R Cirrito
• 金额: $ 19.85万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752688
• 关键词: ATP binding cassette transporter 1; Affect; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloid deposition; Apolipoprotein E; Apolipoproteins; Astrocytes; Bexarotene; Biological; Brain; Cardiovascular Diseases; Cells; Chemicals; Cholesterol; Computer Simulation; Disease; Dose; Functional disorder; Genes; Goals; Human; Inflammatory; Ischemia; Late Onset Alzheimer Disease; Lead; Link; Liver X Receptor; Measures; Microdialysis; Neurodegenerative Disorders; Neuropathogenesis; Nuclear Receptors; Pharmacology; Phenotype; Physiological; Population; Production; Protein Isoforms; RXR; Risk Factors; Synaptic plasticity; Testing; Therapeutic; apolipoprotein E-3; apolipoprotein E-4; brain cell; disease phenotype; drug discovery; experimental study; genetic variant; high throughput screening; human disease; in vivo; mouse model; neuroinflammation; novel; response; small molecule; tool

PROJECT SUMMARY Apolipoprotein E (apoE), a cholesterol-transporting apolipoprotein, is critically involved in the pathophysiology of a number of human disorders, including cardiovascular diseases, ischemia and neurodegenerative diseases. Most notably, among the common allele variants of the APOE gene (APOE2, APOE3 and APOE4), the APOE4 allele (encoding apoE4 isoform) underlies the single strongest risk factor for late-onset Alzheimer’s disease (AD). ApoE regulates the clearance, aggregation, and deposition of amyloid-β (Aβ) in an isoform-dependent manner and also regulates other AD-relevant brain functions such as neuroinflammation and synaptic plasticity. ApoE is mainly produced and secreted from astrocytes in the brain. It has been postulated that an increase in the levels of apoE (especially the apoE3 isoform present in the majority of the human population) leads to decreased amyloid levels. Therefore, it is conceivable that an increase of apoE may furnish therapeutic benefits for AD. The idea of pharmacological enhancement of apoE has been tested using several nuclear receptor agonists, such as bexarotene and T0901317(retinoid X receptor (RXR) and liver X receptor (LXR) agonist, respectively). Since these compounds induce a number of genes other than apoE (such as ABCA1) which have widespread physiological effects, it is difficult to pin-point the exact contribution of apoE elevation in AD-associated phenotypic changes in the brain. To this end, we have conducted high throughput screening (HTS) in order to identify novel small molecules that can enhance apoE production in human primary astrocytes. We have identified a number of small molecule hits that can increase apoE levels via previously unknown mechanisms, including ones promoting apoE secretion without co-inducing ABCA1. Using these compounds as chemical tools, we will first confirm pharmacological activities of the identified apoE modulators in vivo and further test to discover compound(s) that can affect AD-like phenotypes in mouse models of AD. Thus, by using physiologically relevant brain cells for HTS, our proposed studies will help not only to establish translational significance of pharmacological modulation of apoE levels in the brain, but also to understand regulatory mechanisms of brain apoE levels which will provide broad translational significance on other apoE-linked human disease pathophysiology. Successful completion of our proposed studies will also lead to the identification of new tool compounds that modulate apoE secretion through previously unknown mechanisms of action in vivo, or that are ideal for further drug discovery efforts.

项目摘要 载脂蛋白E（APOE）是一种胆固醇转运的载脂蛋白，至关重要地参与 许多人类疾病，包括心血管疾病，缺血和神经退行性疾病。 最值得注意的是，在APOE基因的常见等位基因变体中，APOE4（APOE2，APOE3和APOE4） 等位基因（编码APOE4同工型）是阿尔茨海默氏病（AD）的单个强风险因素。 APOE以同工型依赖性方式调节淀粉样β（Aβ）的清除，聚集和沉积 还调节其他与AD相关的大脑功能，例如神经炎症和突触可塑性。 Apoe是 主要由大脑的星形胶质细胞产生和分泌。有人认为水平有所增加 APOE（尤其是大多数人口中存在的APOE3同工型）导致精致 淀粉样蛋白水平。因此，可以想象，APOE的增加可能会为AD提供治疗益处。 使用多个核接收器（例如 Bexarotene和T0901317（分别是类维生素X受体（RXR）和肝X受体（LXR）激动剂）。自从 这些化合物影响具有宽度的apoE（例如ABCA1）以外的许多基因 物理效果，很难确定APOE高程与广告相关的确切贡献 大脑的表型变化。为此，我们进行了高吞吐量筛查（HTS），以便 确定可以增强人类原代星形胶质细胞中APOE产生的新型小分子。我们有 确定了许多小分子命中，可以通过以前未知的机制增加APOE水平， 包括促进APOE分泌的人，而无需共同诱导ABCA1。将这些化合物作为化学工具， 我们将首先确认体内已鉴定的APOE调制器的药物活动，并进一步测试 发现可能影响AD小鼠模型中AD样表型的化合物。那是通过身体上的 有关HTS的相关脑细胞，我们的拟议研究不仅有助于建立翻译意义 大脑中APOE水平的药理调节，但也了解大脑的调节机制 APOE水平将对其他APOE连接的人类疾病提供广泛的转化意义 病理生理学。成功完成我们建议的研究还将导致确定新工具 通过以前未知的体内作用机理来调节APOE分泌的化合物，或 进一步的药物发现工作的理想选择。