ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.
ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.
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DOI：
10.1016/j.neuron.2022.03.004
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发表时间：
2022-04-20
期刊：
影响因子：
16.2
通讯作者：
Bu, Guojun
中科院分区：
文献类型：
--
作者：
Martens, Yuka A.;Zhao, Na;Liu, Chia-Chen;Kanekiyo, Takahisa;Yang, Austin J.;Goate, Alison M.;Holtzman, David M.;Bu, Guojun
载脂蛋白E基因的ε4等位基因是阿尔茨海默病(AD)和其他几种神经退行性疾病(包括路易体痴呆)的强烈遗传风险因素。这三个apoE等位基因编码的蛋白质亚型只在第112和158位氨基酸不同：apoE2(C112，C158)、apoE3(C112，R158)和apoE4(R112，R158)。尽管取得了进展，但尚不清楚这三种异构体之间apoE序列的这些微小氨基酸差异是如何导致对衰老和疾病相关途径的深刻影响的。在这里，我们在AD和年龄相关的认知衰退中提出了一个新的“ApoE级联假说”，即apoE的生化和生物物理性质影响细胞和系统水平的一系列事件，最终影响包括AD在内的衰老相关疾病。因此，针对载脂蛋白E的治疗干预预计将通过解决级联反应的生化阶段而更加有效。在这篇综述中，Marten et al.提出一种新的“载脂蛋白E级联假说”，认为载脂蛋白E的生化和生物物理性质会在细胞和系统水平上影响一系列事件，最终导致阿尔茨海默病和与年龄相关的认知能力下降。
The ε4 allele of the apolipoprotein E gene (APOE4) is a strong genetic risk factor for Alzheimer’s disease (AD) and several other neurodegenerative conditions including Lewy body dementia (LBD). The three APOE alleles encode protein isoforms which differ from one another only at amino acid positions 112 and 158; apoE2 (C112, C158), apoE3 (C112, R158), and apoE4 (R112, R158). Despite progress, it remains unclear how these small amino acid differences in apoE sequence among the three isoforms lead to profound effects on aging and disease-related pathways. Here, we propose a novel “ApoE Cascade Hypothesis” in AD and age-related cognitive decline that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels ultimately impacting aging-related pathogenic conditions including AD. As such, apoE-targeted therapeutic interventions are predicted to be more effective by addressing the biochemical phase of the cascade. In this review, Martens et al. propose a novel “ApoE Cascade Hypothesis” that the biochemical and biophysical properties of apoE impact a cascade of events at the cellular and systems levels ultimately leading to Alzheimer’s disease and age-related cognitive decline.
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