Impact of APOE Christchurch mutation on amyloid burden and tau pathology

项目摘要/摘要 载脂蛋白E(ApoE)是大脑中的一种主要载脂蛋白，通过细胞表面传递胆固醇和脂类 受体和维持脂类内环境平衡。载脂蛋白E基因多态也与糖尿病的遗传风险因素有关 阿尔茨海默病(AD)。几十年来，APOE2一直被认为是最具保护性的APOE亚型 主要的3种载脂蛋白E亚型，而载脂蛋白4在人和小鼠动物中加速AD的病理 模特们。此外，最近的病例报告显示，APOE3克赖斯特彻奇突变，一种罕见的APOE变异， 可能是一种有益的基因修饰物，可以对抗AD的进展。然而，APOE的确切功能 克赖斯特彻奇突变及其在AD病理中的作用尚不清楚。 载脂蛋白E亚型在淀粉样蛋白-β(A-β)的病理过程中具有不同的作用，已有大量研究表明，载脂蛋白E亚型在淀粉样变性的发病机制中起着重要作用。 载脂蛋白E的脂化状态与Aβ沉积有关。除了β病理学，最近的研究 提示APOE亚型调节tau的病理和tau相关的神经变性。在这项提案中，我们 目的探讨APOE克赖斯特彻奇突变在AD发病中的作用。我们假设APOE 克赖斯特彻奇突变通过调节载脂蛋白E的脂化作用，提供了对抗AD进展的有益效果。 ApoE克赖斯特彻奇突变可能同时影响Aβ斑块负担和tau相关病理。这样做的目的是 关于确定APOE克赖斯特彻奇突变如何相互作用以抑制由 Aβ和Tau。

Project Summary/Abstract Apolipoprotein E (APOE), a major apolipoprotein in the brain, transfers cholesterol and lipids through cell surface receptors and maintains lipid homeostasis. APOE polymorphism is also linked to the genetic risk factor for Alzheimer’s disease (AD). For decades, APOE2 has been considered the most protective APOE isoform among the major 3 APOE isoforms, whereas APOE4 accelerates AD pathologies in both human and mouse animal models. In addition, the recent case report has shown that APOE3 Christchurch mutation, a rare APOE variant, could be a beneficial genetic modifier against AD progression. However, the exact function of the APOE Christchurch mutation and its role in AD pathologies are not clearly understood. It has been well studied that APOE isoforms have differential effects on amyloid-β (Aβ) pathology and the lipidated status of APOE has been involved in Aβ deposition. In addition to Aβ pathology, the recent study suggested APOE isoform modulates tau pathology and tau-related neurodegeneration. In this proposal, we pursue to investigate the roles of APOE Christchurch mutation in AD pathologies. We hypothesized that APOE Christchurch mutation provides beneficial effects against AD progression by modulating lipidation of APOE. APOE Christchurch mutation could impact both Aβ plaque burden and tau-related pathology. The goal of this proposal to determine how APOE Christchurch mutation interact to suppress the pathologies caused by Aβ and Tau.