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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Abeta clearance Abeta synthesis Adverse effects Affect Age Agonist Alleles Alzheimer&apos s Disease Alzheimer&apos 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

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项目摘要

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（APOE4）基因的遗传是迄今为止确定的强遗传危险因素阿尔茨海默氏病（AD）。尽管APOE4影响AD的发展的机制是尚未完全理解，令人信服的证据表明APOE4的致病作用是介导的通过与脂质相关的途径。与更常见的APOE3同工型相比，APOE4在大脑中高密度脂蛋白（HDL）的脂质和形成。遗传和药理已显示APOE脂质/HDL形成途径的操作可以调节认知功能和 AD动物模型中的神经病理学。但是，与这些治疗相关的不利副作用是重大关注。在本提案中，我们试图复制独特的，良好的特征，并且临床测试的HDL模拟肽可以逆转APOE4脂质缺乏和与广告相关的神经病理学。这种小的合成肽由18种氨基酸组成，没有直接的序列同源蛋白质但模仿HDL相关的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，这种辣椒具有HDL的血管保护特性。它有进入人类早期的心血管疾病临床试验，没有显示出安全问题。在初步研究，我们发现该肽促进细胞胆固醇外排，从而增强了APOE 星形胶质细胞和小胶质细胞的分泌和脂质，以及抵抗淀粉样β（Aβ）诱导的抑制神经胶质细胞的APOE分泌和脂质。另外，该肽抑制Aβ聚集，促进 Aβ在人类血脑屏障（BBB）的细胞模型中的运输，并有效地穿透BBB 在老鼠中。这是我们假设使用这种独特肽治疗可以挽救脑apoe4脂质和功能性定义并减轻AD中与APOE4相关的神经病理学。该假设将由两个检验人类APOE4靶向替换（TR）小鼠的具体目的，该小鼠概括了APOE的功能缺陷。4 在没有Aβ病理学的情况下，与人类ApoE3-TR小鼠相比，人类中的载体。临床前研究的积极结果预计将对研究领域产生重大的总体影响 AD的项目将为开发基于HDL的创新疗法提供概念证明靶向APOE4病理机制的方法。