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.

项目摘要 载脂蛋白E4（apoE 4）基因的遗传是迄今为止发现的晚期乳腺癌最强的遗传风险因素。 阿尔茨海默病（AD）。虽然apoE 4影响AD发生的机制是 尽管尚未完全了解，但有令人信服的证据表明，apoE 4的致病作用是介导的， 通过脂质相关的途径。与更常见的apoE 3亚型相比，apoE 4在以下方面表现出缺陷： 脂质化和脑中高密度脂蛋白（HDL）的形成。遗传和药理学 apoE脂化/HDL形成途径的操作已显示调节认知功能， AD动物模型中的神经病理学。然而，与这些治疗相关的不良副作用是 重大关切。在目前的建议中，我们试图重新利用一个独特的，特点鲜明的， 临床测试的HDL模拟肽逆转apoE 4脂质化缺陷和AD相关的神经病理学。 这种小的合成肽由18个氨基酸组成，与天然的肽没有直接的序列同源性。 蛋白质，但模仿独特的脂质相互作用的结构中包含的HDL相关载脂蛋白。 以前的研究已经证明，这种肽具有血管保护特性的HDL。它有 进入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 初步研究，我们发现这种肽促进细胞胆固醇流出，增强apoE， 从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， 胶质细胞的apoE分泌和脂化。此外，这种肽抑制Aβ聚集，促进A β的形成， Aβ转运穿过人血脑屏障（BBB）的细胞模型，并有效穿透BBB 对小鼠因此，我们假设用这种独特的肽治疗可以挽救脑apoE 4脂化， 功能缺陷和减轻AD中apoE 4相关的神经病理学。这一假设将由两个 在人apoE 4靶向替代（TR）小鼠中的特定目的，重现apoE 4的功能缺陷 携带者在人类中，与人类apoE 3-TR小鼠在不存在或存在Aβ病理学的情况下进行比较。 这项临床前研究的积极结果预计将在研究领域产生重大的整体影响 因为该项目将为开发创新的基于HDL的治疗药物提供概念证明 靶向apoE 4病理机制的方法。