Reshaping ApoE4 and Alzheimer's Brains with ApoE2

项目摘要 我们在本申请中提出的研究旨在将我们最近对 与人载脂蛋白E2（ApoE 2）基因型相关的神经保护机制， 预防和治疗阿尔茨海默病（AD）的治疗机会。总体假设 将人ApoE 2蛋白引入高风险ApoE 4和AD脑中， 脑老化或疾病的发病机制，通过增强大脑的弹性， 糖酵解代谢，其随后改善葡萄糖利用、蛋白质稳态， 突触活动在筹备过程中，我们取得了三个重要里程碑，这对 这种转化奋进：（1）开发用于生产生理相关的方法， 和具有生物学活性的人相容性重组ApoE 2（rhApoE 2）糖蛋白 功能与内源性人ApoE 2相当;（2）开发非侵入性方法 用于通过调节钙粘蛋白在血脑上的相互作用向脑递送rhApoE 2糖蛋白 屏障（BBB），其在ApoE 4脑中诱导神经保护性信号传导;和（3）开发新的 分别靶向人散发性（sAD）和家族性AD的人源化敲入小鼠模型 (fAD)，预计将为将实验室成功转化为 床边拟议的研究将追求三个具体目标。在初步成功的基础上， 第一个目的是确定用于递送rhApoE 2的治疗最佳方案 糖蛋白，其将导致rhApoE 2在整个皮质和海马区域沉积， 上调脑糖酵解代谢而不引起不良反应。的目的 第二个目的是评估rhApoE 2递送的治疗效果，与年龄和 在表达生理学信号的人源化小鼠模型中， 人ApoE 3或ApoE 4和人野生型APP蛋白的水平。第三个目标是 在表达生理水平的人ApoE 3或ApoE 4的人源化小鼠模型中研究 和人突变APP蛋白，以评估rhApoE 2递送对脑的治疗影响 与fAD相关的变化，以及rhApoE 2介导的效应如何通过联合用药进行修饰 年龄、性别、ApoE基因型和疾病状态。我们对拟议研究的总体目标是 确立以脑代谢恢复力为目标作为疾病改善策略的可行性， 生成关于基于rhApoE 2的蛋白质疗法是否可能 发展成为一种有效和安全的AD干预措施。

PROJECT SUMMARY The research we propose in this application seeks to translate our recent understanding of the neuroprotective mechanism associated with the human apolipoprotein E2 (ApoE2) genotype into a therapeutic opportunity to prevent and treat Alzheimer’s disease (AD). The overarching hypotheses are that introduction of human ApoE2 protein into high-risk ApoE4 and AD brains positively alters the course of brain aging or disease pathogenesis by bolstering brain resilience through enhanced glycolytic metabolism, which subsequently improves glucose utilization, protein homeostasis, and synaptic activity. In preparation, we have achieved three major milestones critical to the success of this translational endeavor: (1) development of a method for the production of physiologically relevant and human-compatible recombinant ApoE2 (rhApoE2) glycoprotein that possesses biological functionality comparable to endogenous human ApoE2; (2) development of a noninvasive approach for brain delivery of rhApoE2 glycoprotein via modulation of cadherin interactions on the blood-brain barrier (BBB), which induces neuroprotective signaling in ApoE4 brains; and (3) development of novel humanized knock-in mouse models that respectively target human sporadic (sAD) and familial AD (fAD), which are expected to provide high predictive validity for translating bench successes to bedside. The proposed studies will pursue three specific aims. Building on our initial success, the objective of the first aim is to determine the therapeutically optimal regimen for delivery of rhApoE2 glycoprotein that will result in deposition of rhApoE2 throughout cortical and hippocampal regions and upregulation of brain glycolytic metabolism without eliciting adverse reactions. The objective of the second aim is to evaluate the therapeutic impact of rhApoE2 delivery, in combination with age and sex, on brain changes associated with sAD in humanized mouse models that express physiological levels of human ApoE3 or ApoE4 and human wild-type APP proteins. The third aim will be investigated in humanized mouse models that express physiological levels of human ApoE3 or ApoE4 and human mutant APP proteins to evaluate the therapeutic impact of rhApoE2 delivery on brain changes associated with fAD, and how the rhApoE2-mediated effects are modified by a combination of age, sex, ApoE genotype, and disease status. Our overall goals for the proposed research are to establish the plausibility of targeting brain metabolic resilience as a disease-modifying strategy and generate proof of concept as to whether a rhApoE2-based protein therapy can potentially be developed into an effective and safe intervention for AD.