Testing a Unique HDL Mimetic Peptide to Reverse ApoE4 Lipidation Deficiency and Alzheimer's Neuropathology

项目总结 载脂蛋白E4(ApoE4)基因的遗传是迄今为止发现的最强的晚期遗传风险因素 起病的阿尔茨海默病(AD)。尽管载脂蛋白E4影响AD发生的机制是 尚未完全了解，令人信服的证据表明apoE4的致病作用是由 通过与脂质相关的途径。与更常见的apoE3亚型相比，apoE4在 大脑中高密度脂蛋白(高密度脂蛋白)的脂化和形成。遗传学和药理学 载脂蛋白E脂化/高密度脂蛋白形成途径的操作已被证明调节认知功能和 AD动物模型的神经病理学研究。然而，与这些治疗相关的不良副作用有 非常令人担忧。在本提案中，我们尝试重新调整一个独特的、具有良好特征的和 临床试验高密度脂蛋白模拟肽逆转载脂蛋白E4脂化缺乏症和AD相关神经病理。 这一小段合成肽由18个氨基酸组成，与天然多肽没有直接序列同源性。 蛋白质，但模仿包含在高密度脂蛋白相关的载脂蛋白中的独特的脂相互作用结构。 先前的研究表明，这种多肽具有与高密度脂蛋白一样的血管保护作用。它有 进入了心血管疾病的早期人体临床试验，没有显示出安全性问题。在……里面 初步研究发现，该肽可促进细胞内胆固醇外流，增强载脂蛋白E 星形胶质细胞和小胶质细胞的分泌和脂化，并对抗淀粉样蛋白β(Aβ)诱导的抑制 胶质细胞的载脂蛋白分泌和脂化作用。此外，该肽还抑制Aβ聚集，促进 β通过人血脑屏障细胞模型的转运，并有效地穿透血脑屏障 在老鼠身上。因此，我们假设，用这种独特的多肽治疗可以挽救脑内载脂蛋白E4的脂化和 AD患者的功能缺陷和减轻载脂蛋白E4相关的神经病理。这一假设将由两个人来检验 人apoE4靶向替换(Tr)小鼠的特异性靶点，概括了apoE4的功能缺陷 与没有或存在β病理的人类载脂蛋白E3-tr小鼠相比，人类中的携带者。 这项临床前研究的积极结果预计将对研究领域产生重大的整体影响。 该项目将为开发基于高密度脂蛋白的创新疗法提供概念证明 针对载脂蛋白E4病理机制的研究方法。

PROJECT SUMMARY Inheritance of the apolipoprotein E4 (apoE4) gene is the strongest genetic risk factor identified to date for late onset Alzheimer’s disease (AD). Although the mechanisms by which apoE4 affects the development of AD are not completely understood, compelling evidence indicates that the pathogenic effects of apoE4 are mediated by lipid-related pathways. Compared with the more common apoE3 isoform, apoE4 exhibits deficiency in lipidation and formation of high density lipoproteins (HDL) in the brain. Genetic and pharmacological manipulations of apoE lipidation/HDL formation pathways have been shown to modulate cognitive function and neuropathology in animal models of AD. However, adverse side effects associated with those treatments are of significant concern. In the present proposal, we attempt to repurpose a unique, well characterized, and clinically tested HDL mimetic peptide to reverse apoE4 lipidation deficiency and AD-related neuropathology. This small synthetic peptide consists of 18 amino acids and has no direct sequence homology to natural proteins but mimics the unique lipid-interacting structure contained in HDL-associated apolipoproteins. Previous studies have demonstrated that this peptide possesses vascular protective properties as HDL. It has advanced into early human clinical trials for cardiovascular disease and showed no safety concerns. In preliminary studies, we have found that this peptide promotes cellular cholesterol efflux, enhances apoE secretion and lipidation from astrocytes and microglia, and counteracts amyloid β (Aβ)-induced suppression on apoE secretion and lipidation by glial cells. In addition, this peptide inhibits Aβ aggregation, promotes the transport of Aβ across a cellular model of human blood-brain barrier (BBB), and efficiently penetrates the BBB in mice. Thus, we hypothesize that treatment with this unique peptide can rescue brain apoE4 lipidation and functional deficits and mitigate apoE4-associated neuropathology in AD. This hypothesis will be tested by two specific aims in human apoE4-targeted replacement (TR) mice, which recapitulate functional deficits of apoE4 carriers in humans, compared with human apoE3-TR mice in the absence or presence of Aβ pathology. Positive results from this preclinical study are expected to have a significant overall impact in the research field of AD as this project will provide a proof of concept for developing innovative HDL-based therapeutic approaches targeting apoE4 pathological mechanisms.