ApoE isoform-specific therapy for Alzheimer disease

描述（由申请人提供）：载脂蛋白E （APOE）基因的¿4等位基因与更常见的¿3等位基因相比，是迟发性阿尔茨海默病（AD）最强的遗传风险因素。动物模型和人类的研究表明，与apoE3相比，apoE4同时表现出功能丧失和毒性功能获得。在调节淀粉样蛋白病理方面，apoE4在介导淀粉样蛋白- (A)肽的清除方面不如apoE3有效，而在促进A -聚集方面更占优势。在A¿途径之外，apoE4在运输脂质和支持突触方面也效率较低。这些研究引出了一个重要但尚未解决的问题，即在AD治疗中是增加还是降低apoE水平更好。由于没有研究解决调节apoE表达对成年小鼠的影响，我们开发了新的动物模型，允许诱导和细胞类型特异性表达apoE3或apoE4。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，本研究的主要目的是研究apoE3或apoE4表达的增加或减少，无论有无淀粉样蛋白病理，如何影响apoE亚型相关功能、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水平分别代表了治疗和/或预防AD的有希望的策略。我们提出三个具体目标来检验我们的假设。在Aim 1中，我们将研究apoE3或apoE4在不同年龄和不同淀粉样蛋白病理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，没有或具有淀粉样蛋白模型APP/PS1背景。在Aim 2中，我们将研究apoE3或apoE4在不同年龄和不同淀粉样蛋白病理阶段的表达下调如何影响A¿代谢、斑块沉积、突触和行为。这些研究将在APP/PS1缺失或存在的apoE敲除小鼠背景下进行。最后，在Aim 3中，我们将评估apoE3或apoE4的外周表达如何影响大脑代谢、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载脂蛋白e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成人大脑或外周apoE亚型的上调或下调如何影响AD的发病机制。这些研究结果将为基于载脂蛋白的AD预防和治疗提供机制见解。

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.