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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：
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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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。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，也表现出毒性功能获得。在调节淀粉样蛋白病理方面，apoE4在介导淀粉样多肽的清除方面不如apoE3有效，而在促进A？聚集方面则更具优势。在A？途径之外，apoE4在运输脂质和支持突触方面的效率也较低。这些研究导致了一个重要但尚未回答的问题，即在AD治疗中，提高或降低载脂蛋白E水平哪一个更好。由于还没有关于调节成年小鼠apoE表达的影响的研究，我们开发了新的动物模型，允许apoE3或apoE4的可诱导和细胞类型特异性表达。为了利用这些独特的动物模型，我们建立了生化、病理和行为分析，以区分apoE3和apoE4相关的表型。因此，这项建议的主要目的是研究apoE3或apoE4表达的增加或减少是如何影响apoE亚型相关功能、突触和行为的。我们的总体假设是，降低载脂蛋白4携带者的载脂蛋白E水平和增加载脂蛋白3携带者的载脂蛋白E水平分别代表了有希望的AD治疗和/或预防策略。我们提出了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的不同阶段过度表达如何影响A？代谢、斑块沉积、突触和行为。这些研究将在没有或有淀粉样蛋白模型APP/PS1背景的apoE3靶向替换(Tr)小鼠或apoE4-tr小鼠的背景下进行。在目标2中，我们将研究在不同年龄和淀粉样蛋白病理的不同阶段apoE3或apoE4表达下调如何影响A？代谢、斑块沉积、突触和行为。这些研究将在没有APP/PS1或存在APP/PS1的apoE基因敲除小鼠的背景下进行。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没有apoE表达的情况下进行。总之，我们的研究将首次测试不同年龄和淀粉样蛋白病理不同阶段的成人大脑或外周apoE亚型的上调或下调如何影响AD的发病。这些研究的结果将为基于载脂蛋白E的AD的预防和治疗提供机制方面的见解。