Abstract

The apolipoprotein E (APOE) involved in lipid metabolism participates in the clearance and deposition of the amyloid-beta peptide of the Alzheimer’s disease (AD). The isoform APOE4 with the ARG112 mutation is the main genetic risk for the late-onset AD. Herein, using both molecular dynamics and quantum mechanics, the binding mechanisms of APOE4 leading to the AD are unraveled and now available for drug design. The binding affinities of APOE4 compared to the normal APOE3 are computed for the four cases: the bare APOE, APOE bound to the amyloid-beta peptide, APOE bound to a lipid nanoparticle mimicking the lipid effects and APOE bound to both amyloid-beta peptide and lipid nanoparticle. When APOE4 is bound to the amyloid-beta peptide, its structure becomes misfolded. Its binding free energy is higher than that of APOE3 in complex with the amyloid-beta peptide. Salt bridges for the APOE correct folding are missing in APOE4, resulting in an increased deposition of the amyloid-beta peptide, compared to APOE3, which can lead to the AD. When both amyloid-beta peptide and lipid nanoparticle are bound to APOE4, there is a detrimental cooperativity between the two misfolding effects, and amyloid-beta peptide deposition is even more significant. Immunotherapies with anti-APOE4 antibodies are promising for drug design against APOE4, but only non-lipidated APOE4 can be targeted. Gene editing is an interesting research alternative, because the genes APOε₄ and APOε₃ differ by only one nucleotide.

摘要

参与脂质代谢的载脂蛋白 E (APOE) 参与阿尔茨海默病 (AD) 的淀粉样蛋白-β 肽的清除和沉积。具有 ARG112 突变的亚型 APOE4 是迟发性 AD 的主要遗传风险。在这里，利用分子动力学和量子力学，揭示了导致 AD 的 APOE4 的结合机制，现在可用于药物设计。计算了四种情况下 APOE4 与正常 APOE3 的结合亲和力：裸 APOE、与淀粉样蛋白-β 肽结合的 APOE、与模拟脂质作用的脂质纳米颗粒结合的 APOE 和与淀粉样蛋白-β 肽结合的 APOE 和脂质纳米颗粒。当 APOE4 与淀粉样蛋白-β 肽结合时，其结构会发生错误折叠。其结合自由能高于与β-淀粉样肽复合的APOE3。与 APOE3 相比，APOE4 中缺少用于 APOE 正确折叠的盐桥，导致淀粉样蛋白-β 肽的沉积增加，从而导致 AD。当β-淀粉样肽和脂质纳米颗粒都与APOE4结合时，两种错误折叠效应之间存在不利的协同作用，β-淀粉样肽沉积更为显着。具有抗 APOE4 抗体的免疫疗法有望用于针对 APOE4 的药物设计，但只能靶向非脂化 APOE4。基因编辑是一个有趣的研究选择，因为基因 APO 这可能导致AD。当β-淀粉样肽和脂质纳米颗粒都与APOE4结合时，两种错误折叠效应之间存在不利的协同作用，β-淀粉样肽沉积更为显着。具有抗 APOE4 抗体的免疫疗法有望用于针对 APOE4 的药物设计，但只能靶向非脂化 APOE4。基因编辑是一个有趣的研究选择，因为基因 APO 这可能导致AD。当β-淀粉样肽和脂质纳米颗粒都与APOE4结合时，两种错误折叠效应之间存在不利的协同作用，β-淀粉样肽沉积更为显着。具有抗 APOE4 抗体的免疫疗法有望用于针对 APOE4 的药物设计，但只能靶向非脂化 APOE4。基因编辑是一个有趣的研究选择，因为基因 APOε ₄和 APO ε ₃仅相差一个核苷酸。