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（由应用提供）：与更常见的3等位基因相比，载脂蛋白E（APOE）基因的4等位基因是晚期阿尔茨海默氏病（AD）的强遗传危险因素（AD）。在动物模型和人类中的研究表明，与APOE3相比，APOE4既表现出功能丧失和激素功能。在调节淀粉样蛋白病理学时，APOE4在介导淀粉样蛋白（A e）肽的清除率方面的效率较低，并且在促进A聚集方面更有主导。在A途径之外，APOE4在运输脂质和支撑突触方面的效率也较低。这些研究导致了一个重要但没有回答的问题，即在AD疗法中是否会更好地提高或降低APOE水平。由于尚未有研究调节APOE表达在成年小鼠中的影响，因此我们开发了新的动物模型，从而允许APOE3或APOE4的诱导型和细胞类型的特异性表达。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。这是该提案的主要目标是研究有或没有淀粉样病理学的APOE3或APOE4表达的增加或减少如何影响与APOE同工型相关的功能，突触和行为。我们的总体假设是，APOE4载体中的APOE水平降低，分别代表AD的承诺治疗和/或预防策略的APOE3载体中的APOE水平提高。我们提出了三个特定的目的来检验我们的假设。在AIM 1中，我们将研究APOE3或APOE4在不同年龄和淀粉样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。这些研究将在没有淀粉样蛋白模型APP/PS1背景的情况下，在APOE3靶向替换（TR）小鼠或APOE4-TR小鼠的背景下进行。在AIM 2中，我们将研究APOE3或APOE4表达在不同年龄和淀粉样病理学不同阶段的下调如何影响A代谢，斑块沉积，突触和行为。这些研究将在不存在或存在APP/PS1的情况下在APOE敲除小鼠的背景下进行。最后，在AIM 3中，我们将评估APOE3或APOE4的周围表达如何影响大脑A型代谢，斑块沉积，突触，行为和心血管健康。这些研究将在大脑中没有APOE表达的情况下进行。总之，我们的研究将首次测试在不同年龄和淀粉样蛋白病理学的不同阶段，成年大脑或外围的APOE同工型的上调或下调如何影响AD发病机理。这些研究的结果将为基于APOE的AD预防和治疗提供机械见解。