Reshaping ApoE4 and Alzheimer's Brains with ApoE2

项目概要 我们在本申请中提出的研究旨在转化我们最近对 与人类载脂蛋白 E2 (ApoE2) 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 将人类 ApoE2 蛋白引入高风险 ApoE4 和 AD 大脑中会积极改变 通过增强大脑恢复能力来治疗大脑衰老或疾病发病机制的过程 糖酵解代谢，随后提高葡萄糖利用率、蛋白质稳态和 突触活动。在准备过程中，我们已经实现了对成功至关重要的三个重要里程碑 这一转化努力的核心：（1）开发一种生理学生产方法 相关且与人类相容的重组 ApoE2 (rhApoE2) 糖蛋白，具有生物学特性 功能与内源性人 ApoE2 相当； (2) 开发无创方法 通过调节血脑上的钙粘蛋白相互作用来向大脑输送 rhApoE2 糖蛋白 屏障 (BBB)，在 ApoE4 大脑中诱导神经保护信号传导； (3) 小说的开发 分别针对人类散发性 (SAD) 和家族性 AD 的人源化敲入小鼠模型 （fAD），预计将提供高度的预测有效性，将实验室的成功转化为 床边。拟议的研究将追求三个具体目标。在我们初步成功的基础上， 第一个目标是确定 rhApoE2 的最佳治疗方案 糖蛋白将导致 rhApoE2 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。该计划的目标 第二个目标是结合年龄和年龄来评估 rhApoE2 递送的治疗影响 性别对表达生理学的人源化小鼠模型中与 SAD 相关的大脑变化的影响 人 ApoE3 或 ApoE4 以及人野生型 APP 蛋白的水平。第三个目标将是 在表达人类 ApoE3 或 ApoE4 生理水平的人源化小鼠模型中进行了研究 和人类突变 APP 蛋白来评估 rhApoE2 递送对大脑的治疗影响 与 fAD 相关的变化，以及如何通过组合改变 rhApoE2 介导的效应 年龄、性别、ApoE 基因型和疾病状况。我们拟议研究的总体目标是 建立以大脑代谢弹性为目标的疾病缓解策略的合理性 产生关于基于 rhApoE2 的蛋白质疗法是否有可能成为现实的概念证明 发展成为一种有效且安全的 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.