Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.
Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.
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载脂蛋白E：从心血管疾病到神经退行性疾病。
DOI：
10.1007/s00109-016-1427-y
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Mahley RW
中科院分区：
文献类型：
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作者：
Mahley RW
载脂蛋白 (apo) E 最初被描述为一种脂质转运蛋白和低密度脂蛋白 (LDL) 受体的主要配体，在胆固醇代谢和心血管疾病中发挥作用。此后，它已成为阿尔茨海默病和其他神经退行性疾病的主要危险因素（致病基因）。三种异构体（apoE2、apoE3 和 apoE4）的结构特征仅因单个氨基酸互换而不同，详细了解它们的结构特征已阐明了它们独特的功能。 ApoE2 和 apoE4 会增加患心脏病的风险：apoE2 会增加致动脉粥样硬化脂蛋白水平（与 LDL 受体结合不良），apoE4 会增加 LDL 水平（它优先与富含甘油三酯的极低密度脂蛋白结合，导致 LDL 受体下调）。 ApoE4 还会增加神经退行性疾病的风险、降低其发病年龄或改变其进展。 ApoE4 可能会导致继发于其异常结构的神经变性，这是由其羧基和氨基末端结构域之间的相互作用（称为结构域相互作用）引起的。当神经元受到压力或损伤时，它们会合成 apoE 来重新分配胆固醇，以进行神经元修复或重塑。然而，由于其结构改变，神经元 apoE4 会经历神经元特异性蛋白水解，产生神经毒性片段 (12-29 kDa)，这些片段逃离分泌途径并导致线粒体功能障碍和细胞骨架改变，包括 tau 磷酸化。 ApoE4 相关的病理可以通过小分子结构校正剂来预防，该校正剂通过将 apoE4 转化为结构和功能上类似于 apoE3 的分子来阻止结构域相互作用。结构校正器是减少心血管和神经系统疾病中 apoE4 病理的潜在治疗方法。
Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease. It has since emerged as a major risk factor (causative gene) for Alzheimer’s disease and other neurodegenerative disorders. Detailed understanding of the structural features of the three isoforms (apoE2, apoE3, and apoE4), which differ by only a single amino acid interchange, has elucidated their unique functions. ApoE2 and apoE4 increase the risk for heart disease: apoE2 increases atherogenic lipoprotein levels (it binds poorly to LDL receptors), and apoE4 increases LDL levels (it binds preferentially to triglyceride-rich, very low density lipoproteins, leading to downregulation of LDL receptors). ApoE4 also increases the risk for neurodegenerative diseases, decreases their age of onset, or alters their progression. ApoE4 likely causes neurodegeneration secondary to its abnormal structure, caused by an interaction between its carboxyl- and amino-terminal domains, called domain interaction. When neurons are stressed or injured, they synthesize apoE to redistribute cholesterol for neuronal repair or remodeling. However, because of its altered structure, neuronal apoE4 undergoes neuron-specific proteolysis, generating neurotoxic fragments (12–29 kDa) that escape the secretory pathway and cause mitochondrial dysfunction and cytoskeletal alterations, including tau phosphorylation. ApoE4-associated pathology can be prevented by small-molecule structure correctors that block domain interaction by converting apoE4 to a molecule that resembles apoE3 both structurally and functionally. Structure correctors are a potential therapeutic approach to reduce apoE4 pathology in both cardiovascular and neurological disorders.