Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Neuron. 2012 Dec 6;76(5):871-85. doi: 10.1016/j.neuron.2012.11.020.
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease and is associated with poor clinical outcome following traumatic brain injury and other neuropathological disorders. Protein instability and an isoform-specific apoE property called domain interaction are responsible for these neuropathological effects. ApoE4 is the most neurotoxic isoform and can induce neuropathology through various cellular pathways. Neuronal damage or stress induces apoE synthesis as part of the repair response; however, when apoE4 is expressed in neurons, its unique conformation makes it susceptible to proteolysis, resulting in the generation of neurotoxic fragments. These fragments cause pathological mitochondrial dysfunction and cytoskeletal alterations. Here, we review data supporting the hypothesis that apoE4 (> apoE3 > apoE2) has direct neurotoxic effects and highlight studies showing that blocking domain interaction reverses these detrimental effects.
载脂蛋白 E4（apoE4）是阿尔茨海默病的主要遗传风险因素，与创伤性脑损伤和其他神经病理学疾病后的不良临床结果相关。蛋白不稳定性和一种称为结构域相互作用的 apoE 特有特性是造成这些神经病理学影响的原因。apoE4 是最具神经毒性的同工型，可通过各种细胞途径诱导神经病理学。神经元损伤或应激诱导 apoE 合成作为修复反应的一部分；然而，当 apoE4 在神经元中表达时，其独特构象使其易受蛋白水解作用的影响，导致产生神经毒性片段。这些片段导致病理性线粒体功能障碍和细胞骨架改变。在这里，我们综述了支持 apoE4（>apoE3>apoE2）具有直接神经毒性作用的假设的数据，并强调了表明阻断结构域相互作用可逆转这些有害作用的研究。
