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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

机译：载脂蛋白E和Alzheimer病：病理学和靶向策略

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摘要

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*epsilon 4 allele conferring an increased risk and the APOE*epsilon 2 allele conferring a decreased risk relative to the common APOE*epsilon 3 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*epsilon 4 carriers. The number of amyloid-beta (A beta)-dependent and A beta-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.
机译：载脂蛋白E（apoE）基因的多态性是晚期疾病（AD）的主要遗传风险决定簇，eAPOE * epsilon 4等位基因赋予了增加的风险和Aposilon 2等位基因，赋予了相比减少的风险共同的apoe * epsilon 3等位基因。来自临床和基础研究的强大证据表明，ApoE4增加了广告风险的主要途径是通过在Apoe * epsilon 4载体的大脑中驾驶早期和更丰富的淀粉样蛋白病理学。已知通过Apoe同种型差异调节的淀粉样蛋白-β（β） - 依赖性和β无关的途径的数量增加。例如，证据积累了ApoE影响TAU病理，TAU介导的神经变性和对AD相关病理学的微胶质反应。此外，ApoE4是致病性的，或者在多种脑稳态途径中表现出降低的效率，包括脂质传输，突触完整性和可塑性，葡萄糖代谢和脑血管功能。在这里，我们审查了临床和基础研究的最新进展，进入Apoe在AD发病机制中的作用。我们还讨论如何使用精密药方法对AD治疗进行靶向的。

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