Impact of APOE Christchurch mutation on amyloid burden and tau pathology

项目总结/摘要 载脂蛋白E（apolipoprotein E，APOE）是脑内主要的载脂蛋白，通过细胞表面转运胆固醇和脂质 受体和维持脂质稳态。APOE多态性也与遗传风险因素有关， 阿尔茨海默病（AD）。几十年来，APOE 2一直被认为是最具保护性的APOE亚型， 主要的3种APOE同种型，而APOE 4加速人类和小鼠动物的AD病理 模型此外，最近的病例报告显示，APOE 3基督城突变，一种罕见的APOE变异， 可能是一种有益的遗传修饰剂，可以防止AD的进展。然而，APOE的确切功能 基督城突变及其在AD病理中的作用尚不清楚。 已经充分研究了APOE同种型对淀粉样蛋白-β（Aβ）病理学的不同影响， APOE的脂化状态与Aβ沉积有关。除了Aβ病理学，最近的研究 提示APOE同种型调节tau病理学和tau相关的神经变性。在本提案中，我们 继续研究APOE基督城突变在AD病理中的作用。我们假设APOE 基督城突变通过调节APOE的脂化作用对AD进展提供有益作用。 APOE基督城突变可影响Aβ斑块负荷和tau相关病理。这个目标 一项旨在确定APOE基督城突变如何相互作用以抑制 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.