Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.,Nature Reviews Neurology

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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies.
Nature Reviews Neurology ( IF 28.2 ) Pub Date : 2019-07-31 , DOI: 10.1038/s41582-019-0228-7
Yu Yamazaki ₁ , Na Zhao ₁ , Thomas R Caulfield ₁ , Chia-Chen Liu ₁ , Guojun Bu ₁

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Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

中文翻译：

载脂蛋白 E 和阿尔茨海默病：病理学和靶向策略。

载脂蛋白 E (APOE) 基因的多态性是迟发性阿尔茨海默病 (AD) 的主要遗传风险决定因素，与常见的 APOE 相比，APOE*ε4 等位基因风险增加，APOE*ε2 等位基因风险降低*ε3 等位基因。来自临床和基础研究的有力证据表明，APOE4 增加 AD 风险的主要途径是通过在 APOE*ε4 携带者的大脑中驱动更早和更丰富的淀粉样蛋白病理。已知受 APOE 异构体差异调节的淀粉样蛋白-β (Aβ) 依赖性和 Aβ 非依赖性途径的数量正在增加。例如，越来越多的证据表明 APOE 影响 tau 病理、tau 介导的神经变性和小胶质细胞对 AD 相关病理的反应。此外，APOE4 要么是致病的，要么在多种脑内稳态途径中表现出降低的效率，包括脂质转运、突触完整性和可塑性、葡萄糖代谢和脑血管功能。在这里，我们回顾了APOE在AD发病机制中作用的临床和基础研究的最新进展。我们还讨论了如何使用精准医学方法靶向 APOE 进行 AD 治疗。

更新日期：2019-08-01

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