ApoE isoform-specific therapy for Alzheimer disease

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apoE 3相比，apoE 4表现出功能丧失和毒性功能获得。在调节淀粉样蛋白病理学中，apoE 4在介导淀粉样蛋白（A）肽清除方面不如apoE 3有效，而在促进A聚集方面更占主导地位。在A？通路之外，apoE 4在转运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治疗中增加或降低apoE水平是否更好。由于还没有研究解决成年小鼠中apoE表达的调节作用，我们已经开发了新的动物模型，允许apoE 3或apoE 4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apoE 3和apoE 4相关表型的生化、病理和行为分析。因此，本提案的主要目标是研究在淀粉样蛋白病变的情况下apoE 3或apoE 4表达的增加或减少如何影响apoE异构体相关的功能、突触和行为。我们的总体假设是，APOE 4携带者中apoE水平的降低和APOE 3携带者中apoE水平的升高分别代表了AD有希望的治疗和/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apoE 3或apoE 4在不同年龄和淀粉样病变的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apoE 3靶向替代（TR）小鼠或apoE 4-TR小鼠的背景下进行，不具有或具有淀粉样蛋白模型APP/PS1背景。在目标2中，我们将研究在不同年龄和淀粉样病变的不同阶段，apoE 3或apoE 4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敲除小鼠的背景下进行，不存在或存在APP/PS1。最后，在目标3中，我们将评估apoE 3或apoE 4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。这些研究将在脑中不存在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病变的不同阶段，apoE亚型在成人大脑或外周中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apoE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.