ApoE isoform-specific therapy for Alzheimer disease

ApoE 异构体特异性治疗阿尔茨海默病

• 批准号: 8608893
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608893
• 关键词: APP-PS1; Address; Adult; Affect; Age; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyloid; Animal Model; Apolipoprotein E; Apolipoproteins; Astrocytes; Atherosclerosis; Behavior; Behavioral; Biochemical; Brain; Breeding; Cardiovascular system; 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; amyloid pathology; apolipoprotein E-3; apolipoprotein E-4; base; cell type; design; experience; genetic risk factor; glucose metabolism; in vivo; insight; lipid metabolism; lipid transport; loss of function; mouse model; novel; particle; public health relevance; synaptic function

DESCRIPTION (provided by applicant): The ¿4 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 ¿3 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-¿ (A¿) peptides and is more dominant in promoting A¿ aggregation. Outside the A¿ 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 A¿ 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 A¿ 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 A¿ 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 3 等位基因相比，载脂蛋白 E (APOE) 基因的 4 等位基因是晚发性阿尔茨海默病 (AD) 最强的遗传风险因素。对动物模型和人类的研究表明，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 在介导淀粉样蛋白-K (AK) 肽的清除方面不如apoE3 有效，但在促进AK 聚集方面更占主导地位。在 A¿ 途径之外，apoE4 在转运脂质和支持突触方面的效率也较低。这些研究引出了一个重要但尚未解答的问题：在 AD 治疗中，提高 ApoE 水平好还是降低 ApoE 水平好？由于尚未有研究探讨调节成年小鼠 apoE 表达的影响，我们开发了新的动物模型，允许 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。因此，该提案的主要目标是研究在有或没有淀粉样蛋白病理的情况下apoE3或apoE4表达的增加或减少如何影响apoE亚型相关的功能、突触和行为。我们的总体假设是，降低 APOE4 携带者的 apoE 水平和增加 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。我们提出三个具体目标来检验我们的假设。在目标 1 中，我们将研究 apoE3 或 apoE4 在不同年龄和淀粉样蛋白病理学不同阶段的过度表达如何影响 A¿ 代谢、斑块沉积、突触和行为。这些研究将在 apoE3 靶向替代 (TR) 小鼠或 apoE4-TR 小鼠的背景下进行，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 apoE3 或 apoE4 表达的下调如何影响 A¿ 代谢、斑块沉积、突触和行为。这些研究将在 apoE 基因敲除小鼠不存在或存在 APP/PS1 的情况下进行。最后，在目标 3 中，我们将评估 apoE3 或 apoE4 的外周表达如何影响大脑 A 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。总之，我们的研究将首次测试成人大脑或外周在不同年龄和不同淀粉样蛋白病理阶段 apoE 亚型的上调或下调如何影响 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。