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.

项目概要 载脂蛋白 E (apoE) 是一种胆固醇转运载脂蛋白，与以下疾病的病理生理学密切相关： 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（APOE2、APOE3 和 APOE4）中，APOE4 等位基因（编码 apoE4 同工型）是晚发性阿尔茨海默病 (AD) 的单一最强危险因素。 ApoE 以异构体依赖性方式调节淀粉样蛋白-β (Aβ) 的清除、聚集和沉积 它还调节其他与 AD 相关的大脑功能，例如神经炎症和 ApoE。 据推测，其主要由大脑中的星形胶质细胞产生和分泌。 apoE（尤其是大多数人群中存在的 apoE3 亚型）导致 因此，可以想象，apoE 的增加可能为 AD 提供治疗益处。 药理增强apoE的想法已经使用几种核受体激动剂进行了测试，例如 贝沙罗汀和 T0901317（分别为类视黄醇 X 受体 (RXR) 和肝 X 受体 (LXR) 激动剂）。 这些化合物诱导除 apoE 之外的许多基因（例如 ABCA1），这些基因广泛存在 生理效应，很难确定 apoE 升高在 AD 相关疾病中的确切贡献 为此，我们进行了高通量筛选（HTS）。 我们发现了可以增强人类原代星形胶质细胞中 apoE 产生的新型小分子。 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分泌而不共同诱导ABCA1的化合物使用这些化合物作为化学工具， 我们将首先确认所鉴定的apoE调节剂的体内药理活性并进一步测试 因此，通过使用生理学方法，发现可以影响 AD 小鼠模型中 AD 样表型的化合物。 HTS 相关的脑细胞，我们提出的研究不仅有助于确定 HTS 的转化意义 大脑中apoE水平的药理调节，同时也了解大脑的调节机制 apoE 水平将为其他与 apoE 相关的人类疾病提供广泛的转化意义 成功完成我们提出的研究也将导致新工具的确定。 通过先前未知的体内作用机制调节 apoE 分泌的化合物，或者 进一步药物发现工作的理想选择。