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）是一种转运胆固醇的载脂蛋白，在肝硬化的病理生理过程中起重要作用。 许多人类疾病，包括心血管疾病、局部缺血和神经变性疾病。 最值得注意的是，在APOE基因的常见等位基因变体（APOE 2、APOE 3和APOE 4）中，APOE 4 等位基因（编码apoE4同种型）是晚发性阿尔茨海默病（AD）的单一最强危险因素。 ApoE以亚型依赖性方式调节β淀粉样蛋白（Aβ）的清除、聚集和沉积 并且还调节其他AD相关的脑功能，例如神经炎症和突触可塑性。ApoE是 主要由大脑中的星形胶质细胞产生和分泌。据推测， apoE（尤其是存在于大多数人群中的apoE 3亚型）的减少导致 淀粉样蛋白水平因此，可以想象，apoE的增加可能为AD提供治疗益处。的 已经使用几种核受体激动剂测试了apoE药理学增强的想法，例如 贝沙罗汀和T0901317（分别为类维生素A X受体（RXR）和肝X受体（LXR）激动剂）。以来 这些化合物诱导除了apoE（如ABCA 1）以外的许多基因， 由于apoE的生理效应，很难确定apoE升高在AD相关性脑卒中中的确切作用。 大脑的表型变化。为此，我们进行了高通量筛选（HTS），以 鉴定可增强人原代星形胶质细胞中apoE产生的新型小分子。我们有 鉴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分泌而不共同诱导ABCA 1的那些。利用这些化合物作为化学工具， 我们将首先在体内证实所鉴定的apoE调节剂的药理学活性，并进一步测试， 发现可以影响AD小鼠模型中AD样表型的化合物。因此，通过使用生理学 相关的脑细胞HTS，我们提出的研究将有助于不仅建立翻译的意义， 药理学调节apoE水平在大脑中，而且还了解大脑的调节机制， apoE水平将对其他apoE相关的人类疾病提供广泛的翻译意义 病理生理学成功完成我们提议的研究还将导致确定新的工具， 通过以前未知的体内作用机制调节apoE分泌的化合物，或 是进一步药物发现的理想选择。