Human apolipoprotein E (apoE) is a 299-amino acid secreted glycoprotein binding cholesterol and phospholipids, and with three common isoforms (APOE ε2, APOE ε3, and APOE ε4). The exact mechanism by which APOE gene variants increase/decrease Alzheimer's disease (AD) risk is not fully understood, but APOE isoforms differently affect brain homeostasis and neuroinflammation, blood–brain barrier (BBB) permeability, glial function, synaptogenesis, oral/gut microbiota, neural networks, amyloid beta (Aβ) deposition, and tau-mediated neurodegeneration. In this perspective, we propose a comprehensive interpretation of APOE-mediated effects within AD pathophysiology, describing some specific cellular, biochemical, and epigenetic mechanisms and updating the different APOE-targeting approaches being developed as potential AD therapies. Intracisternal adeno-associated viral-mediated delivery of APOE ε2 is being tested in AD APOE ε4/ε4 carriers, while APOE mimetics are being used in subjects with perioperative neurocognitive disorders. Other approaches including APOE ε4 antisense oligonucleotides, anti-APOE ε4 monoclonal antibodies, APOE ε4 structure correctors, and APOE–Aβ interaction inhibitors produced positive results in transgenic AD mouse models.

中文翻译：

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载脂蛋白 E 亚型的失衡是否是散发性阿尔茨海默病的病理生理过程的基础？

人载脂蛋白 E (apoE) 是一种由 299 个氨基酸组成的分泌型糖蛋白，结合胆固醇和磷脂，并具有三种常见的亚型（APOE ε2、APOE ε3 和APOE ε4）。APOE基因变异增加/降低阿尔茨海默病 (AD) 风险的确切机制尚不完全清楚，但APOE亚型对大脑稳态和神经炎症、血脑屏障 (BBB) 通透性、神经胶质功能、突触发生、口腔/肠道微生物群的影响不同、神经网络、β 淀粉样蛋白 (Aβ) 沉积和 tau 介导的神经变性。从这个角度来看，我们提出了对APOE的全面解读-AD 病理生理学中的介导效应，描述了一些特定的细胞、生化和表观遗传机制，并更新了不同的APOE -靶向方法，这些方法正在开发中作为潜在的 AD 疗法。脑池内腺相关病毒介导的APOE ε2 递送正在 AD APOE ε4/ε4 携带者中进行测试，而APOE模拟物正用于患有围手术期神经认知障碍的受试者。其他方法，包括APOE ε4 反义寡核苷酸、抗APOE ε4 单克隆抗体、APOE ε4 结构校正剂和APOE –Aβ 相互作用抑制剂，在转基因 AD 小鼠模型中产生了积极的结果。