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

测试独特的 HDL 模拟肽以逆转 ApoE4 脂化缺陷和阿尔茨海默病神经病理学

• 批准号: 9306478
• 负责人: LING LI
• 金额: $ 18.98万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306478
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Abeta clearance; Abeta synthesis; Adverse effects; Affect; Age; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Amino Acids; Amyloid; Amyloid beta-Protein; Animal Experiments; Animal Model; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins; Astrocytes; Behavior; Behavior assessment; Behavioral; Bexarotene; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Cardiovascular Diseases; Cell model; Cerebrum; Cholesterol; Clinical; Clinical Trials; Data; Development; Disease; Exhibits; Family; Fatty Liver; Genes; Genetic; Genotype; Goals; High Density Lipoproteins; Human; Hyperlipidemia; Impaired cognition; Late Onset Alzheimer Disease; Lead; Lipids; Lipoproteins; Liver X Receptor; Mediating; Metabolism; Microglia; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Pharmacology; Phenylalanine; Plasma; Positioning Attribute; Property; Protein Isoforms; Proteins; RXR; RXRA gene; Research; Research Project Grants; Safety; Senile Plaques; Sequence Homology; Structure; Testing; Therapeutic; Therapeutic Agents; Up-Regulation; abeta accumulation; abeta deposition; apolipoprotein E-3; apolipoprotein E-4; base; beta amyloid pathology; cognitive function; design; effective therapy; experience; extracellular; gain of function; genetic risk factor; hyperphosphorylated tau; improved; innovation; lipid metabolism; mouse model; neuropathology; novel therapeutic intervention; overexpression; peptidomimetics; preclinical study; prevent; sex; synthetic peptide; tau Proteins

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.

项目概要 载脂蛋白 E4 (apoE4) 基因的遗传是迄今为止发现的最强的遗传风险因素。 阿尔茨海默病（AD）发作。尽管apoE4影响AD发展的机制尚不清楚 尚未完全了解，令人信服的证据表明 apoE4 的致病作用是介导的 通过脂质相关途径。与更常见的 apoE3 亚型相比，apoE4 在以下方面表现出缺陷： 大脑中高密度脂蛋白（HDL）的脂化和形成。遗传和药理学 apoE 脂化/HDL 形成途径的操作已被证明可以调节认知功能和 AD 动物模型的神经病理学。然而，与这些治疗相关的不良副作用是 重大关切。在目前的提案中，我们试图重新利用一个独特的、特征鲜明的、 临床测试 HDL 模拟肽可逆转 apoE4 脂化缺陷和 AD 相关神经病理学。 这种小合成肽由 18 个氨基酸组成，与天然肽没有直接的序列同源性 蛋白质，但模仿 HDL 相关载脂蛋白中包含的独特脂质相互作用结构。 先前的研究表明，这种肽与 HDL 一样具有血管保护特性。它有 进入了心血管疾病的早期人体临床试验，并且没有显示出任何安全问题。在 初步研究，我们发现这种肽可以促进细胞胆固醇流出，增强apoE 星形胶质细胞和小胶质细胞的分泌和脂化，并抵消淀粉样蛋白 β (Aβ) 诱导的抑制 神经胶质细胞的apoE分泌和脂化。此外，该肽还能抑制 Aβ 聚集，促进 Aβ 跨人类血脑屏障 (BBB) 细胞模型的转运，并有效穿透 BBB 在小鼠中。因此，我们假设用这种独特的肽治疗可以挽救大脑 apoE4 脂化和 功能缺陷并减轻 AD 中与 apoE4 相关的神经病理学。这个假设将由两个人来检验 人类 apoE4 靶向替代 (TR) 小鼠的特定目标，概括了 apoE4 的功能缺陷 人类携带者与在不存在或存在 Aβ 病理学情况下的人类 apoE3-TR 小鼠进行比较。 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 AD 项目，因为该项目将为开发基于 HDL 的创新疗法提供概念证明 针对 apoE4 病理机制的方法。