ApoE isoform-specific therapy for Alzheimer disease

ApoE 异构体特异性治疗阿尔茨海默病

基本信息

批准号：
9104070
负责人：
GUOJUN BU
金额：
$ 32.08万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104070
关键词：
APP-PS1 Abeta clearance Address Adult Affect Age Alleles Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease risk Amino Acids Amyloid Amyloid beta-Protein Animal Model Apolipoprotein E Apolipoproteins Astrocytes Atherosclerosis Behavior Behavioral Biochemical Brain Breeding Cholesterol Clinical Trials Cognition Dementia Deposition Development Down-Regulation Elderly Excision Exhibits Genes Goals Guidelines Health Human Impaired cognition Inflammation Knockout Mice Laboratories Late Onset Alzheimer Disease Lead Lipoproteins Liver Mediating Metabolic Clearance Rate Metabolism Microdialysis Modeling Mus Neurons Outcome Measure Pathogenesis Pathology Pathway interactions Peptides Peripheral Phenotype Plasma Population Prevention strategy Prevention therapy Property Protein Isoforms Proteins Public Health Risk Factors Senile Plaques Staging Structure Synapses Technology Testing Tetanus Helper Peptide Time Up-Regulation abeta accumulation abeta deposition amyloid pathology apolipoprotein E-3 apolipoprotein E-4 base cardiovascular health cell type design experience genetic risk factor glucose metabolism in vivo insight lipid metabolism lipid transport loss of function mouse model new therapeutic target novel overexpression particle synaptic function

项目摘要

DESCRIPTION (provided by applicant): The ϵ4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) compared to the more common ϵ3 allele. Studies in animal models and humans suggest that apoE4 exhibits both loss-of-function and gain-of-toxic-function compared to apoE3. In regulating amyloid pathology, apoE4 is less efficient than apoE3 in mediating the clearance of amyloid-ß (Aß) peptides and is more dominant in promoting Aß aggregation. Outside the Aß pathway, apoE4 is also less efficient in transporting lipid and supporting synapses. These studies led to an important yet unanswered question as to whether it is better to increase or decrease apoE levels in AD therapy. As there have not been studies addressing the effects of modulating apoE expression in adult mice, we have developed new animal models that allow for inducible and cell-type specific expression of apoE3 or apoE4. To take advantage of these unique animal models, we have established biochemical, pathological, and behavioral analyses that distinguish apoE3- and apoE4-related phenotypes. Thus, the major goal of this proposal is to investigate how an increase or decrease of apoE3 or apoE4 expression with or without amyloid pathology affects apoE isoform-related functions, synapses and behavior. Our overall hypothesis is that decreasing apoE levels in APOE4 carriers and increasing apoE levels in APOE3 carriers respectively represent promising treatment and/or preventive strategies for AD. We propose three specific aims to test our hypothesis. In Aim 1, we will examine how over-expression of apoE3 or apoE4 at different ages and at different stages of amyloid pathology affects Aß metabolism, plaque deposition, synapses and behavior. These studies will be carried out in the background of apoE3-targeted replacement (TR) mice or apoE4-TR mice, without or with amyloid model APP/PS1 background. In Aim 2, we will investigate how down-regulation of apoE3 or apoE4 expression at different ages and at different stages of amyloid pathology affects Aß metabolism, plaque deposition, synapses and behavior. These studies will be carried out in the background of apoE knockout mice in the absence or presence of APP/PS1. Finally in Aim 3, we will assess how peripheral expression of apoE3 or apoE4 impacts brain Aß metabolism, plaque deposition, synapses, behavior and cardiovascular health. These studies will be carried out in the absence of apoE expression in the brain. Together, our studies will for the first time test how up-regulation or down-regulation of apoE isoforms in the adult brain or periphery at different ages and at different stages of amyloid pathology affects AD pathogenesis. Results from these studies will provide mechanistic insights for apoE-based AD prevention and therapy.

描述（由申请人提供）：与更常见的 ϵ3 等位基因相比，载脂蛋白 E (APOE) 基因的 ϵ4 等位基因是晚发性阿尔茨海默病 (AD) 最强的遗传风险因素。动物模型和人类研究表明，apoE4。与 apoE3 相比，apoE4 表现出功能丧失和毒性功能增强。在调节淀粉样蛋白病理学方面，apoE4 的效率低于 apoE3。在 Aß 途径之外，apoE4 介导淀粉样蛋白-β (Aß) 肽的清除，并且在促进 Aß 聚集方面更占主导地位，但它在转运脂质和支持突触方面的效率也较低。在 AD 治疗中，最好增加或降低 apoE 水平，因为尚未有研究探讨调节成年小鼠 apoE 表达的影响，因此我们开发了新的动物模型。 apoE3 或 apoE4 的诱导型和细胞类型特异性表达为了利用这些独特的动物模型，我们建立了区分 apoE3 和 apoE4 相关表型的生化、病理和行为分析。研究有或没有淀粉样蛋白病理的 apoE3 或 apoE4 表达的增加或减少如何影响 apoE 同工型相关功能、突触和行为。 APOE4 携带者的 apoE 水平和 APOE3 携带者的 apoE 水平分别代表了有希望的 AD 治疗和/或预防策略。在目标 1 中，我们将研究 apoE3 或 apoE4 的过度表达如何。不同年龄和不同阶段的淀粉样蛋白病理学影响Aß代谢、斑块沉积、突触和行为，这些研究将在apoE3靶向替代（TR）小鼠的背景下进行。或 apoE4-TR 小鼠，无或有淀粉样蛋白模型 APP/PS1 背景在目标 2 中，我们将研究不同年龄和不同淀粉样蛋白病理阶段的 apoE3 或 apoE4 表达下调如何影响 Aß 代谢、斑块沉积、突触。这些研究将在不存在或存在 APP/PS1 的情况下在 apoEout 敲除小鼠的背景下进行。最后，在目标 3 中，我们将评估 APP/PS1 的外周表达。 apoE3 或 apoE4 影响大脑 Aß 代谢、斑块沉积、突触、行为和心血管健康。这些研究将在大脑中缺乏 apoE 表达的情况下进行，我们的研究将首次测试如何上调或下调。 -成人大脑或外周不同年龄和淀粉样蛋白病理学不同阶段的 apoE 亚型的调节影响 AD 发病机制，这些研究的结果将为基于 apoE 的 AD 预防和治疗提供机制见解。治疗。