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

项目总结 载脂蛋白E(ApoE)是一种胆固醇转运的载脂蛋白，在高血压的病理生理过程中起重要作用。 一些人类疾病，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亚型)是晚发性阿尔茨海默病(AD)的单一最强危险因素。 载脂蛋白E以异构体依赖的方式调节淀粉样蛋白β(Aβ)的清除、聚集和沉积 还调节其他与AD相关的大脑功能，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，二氧化碳浓度的增加 载脂蛋白E(尤其是大多数人群中存在的载脂蛋白E3亚型)的减少导致 淀粉样蛋白水平。因此，可以想象，载脂蛋白E的增加可能为AD提供治疗益处。这个 药物增强载脂蛋白E的想法已经用几种核受体激动剂进行了测试，例如 贝沙罗汀和T0901317(分别为维甲酸X受体(RXR)和肝X受体(LXR)激动剂)。自.以来 这些化合物诱导了除载脂蛋白E以外的许多基因(如ABCA1)，这些基因具有广泛的 生理效应，很难准确地指出载脂蛋白E升高在AD相关性中的确切贡献 大脑的表型变化。为此，我们进行了高通量筛选(HTS)，以 识别能够促进人类原代星形胶质细胞产生载脂蛋白E的新的小分子。我们有 确定了一些可以通过先前未知的机制增加载脂蛋白E水平的小分子撞击， 包括那些促进载脂蛋白E分泌而不共诱导ABCA1的基因。使用这些化合物作为化学工具， 我们将首先确认已确定的载脂蛋白E调节剂在体内的药理活性，并进一步测试 在AD小鼠模型中发现可影响AD样表型的化合物(S)。因此，通过使用生理上的 对于HTS的相关脑细胞，我们提出的研究将不仅有助于建立 药物对脑内载脂蛋白E水平的调节，也是为了了解大脑的调节机制 载脂蛋白E水平将为其他与载脂蛋白E相关的人类疾病提供广泛的翻译意义 病理生理学。成功完成我们拟议的研究还将导致确定新的工具 通过先前未知的体内作用机制调节载脂蛋白E分泌的化合物，或者是 非常适合于进一步的药物发现工作。

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.