载脂蛋白 E 级联假说在阿尔茨海默病及相关痴呆发病机制中的作用。
ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias.
机构信息
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Division of Neuroscience, National Institute on Aging, Bethesda, MD, USA.
出版信息
Neuron. 2022 Apr 20;110(8):1304-1317. doi: 10.1016/j.neuron.2022.03.004. Epub 2022 Mar 16.
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 that 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, which states 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.
载脂蛋白 E 基因（APOE）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的强遗传风险因素，包括路易体痴呆（LBD）。这三个 APOE 等位基因编码的蛋白异构体仅在氨基酸位置 112 和 158 处有所不同：apoE2（C112，C158），apoE3（C112，R158）和 apoE4（R112，R158）。尽管取得了进展，但仍不清楚这三种异构体中 apoE 序列中的这些小氨基酸差异如何导致对衰老和与疾病相关的途径产生深远影响。在这里，我们在 AD 和与年龄相关的认知能力下降中提出了一个新的“apoE 级联假说”，该假说指出 apoE 的生化和物理特性会影响细胞和系统水平上的一系列事件，最终影响与衰老相关的致病情况，包括 AD。因此，通过解决级联的生化阶段，靶向 apoE 的治疗干预措施预计会更有效。
Zotero 插件