ApoE4-specific Misfolded Intermediate Identified by Molecular Dynamics Simulations

The increased risk of developing Alzheimer’s disease (AD) is associated with the APOE gene, which encodes for three variants of Apolipoprotein E, namely E2, E3, E4, differing only by two amino acids at positions 112 and 158. ApoE4 is known to be the strongest risk factor for AD onset, while ApoE3 and ApoE2 are considered to be the AD-neutral and AD-protective isoforms, respectively. It has been hypothesized that the ApoE isoforms may contribute to the development of AD by modifying the homeostasis of ApoE physiological partners and AD-related proteins in an isoform-specific fashion. Here we find that, despite the high sequence similarity among the three ApoE variants, only ApoE4 exhibits a misfolded intermediate state characterized by isoform-specific domain-domain interactions in molecular dynamics simulations. The existence of an ApoE4-specific intermediate state can contribute to the onset of AD by altering multiple cellular pathways involved in ApoE-dependent lipid transport efficiency or in AD-related protein aggregation and clearance. We present what we believe to be the first structural model of an ApoE4 misfolded intermediate state, which may serve to elucidate the molecular mechanism underlying the role of ApoE4 in AD pathogenesis. The knowledge of the structure for the ApoE4 folding intermediate provides a new platform for the rational design of alternative therapeutic strategies to fight AD.阿尔茨海默病（Alzheimer’s Disease，AD）的发病风险升高与APOE基因相关，该基因编码载脂蛋白E（Apolipoprotein E）的三种变体，即E2、E3、E4，三者仅在112和158位氨基酸存在差异。已知ApoE4是AD发病最强的风险因子，而ApoE3与ApoE2分别被视为AD中性亚型与AD保护性亚型。已有研究假说提出，ApoE亚型可通过亚型特异性的方式，调控ApoE生理结合伴侣及AD相关蛋白的稳态，进而参与AD的发生发展。本研究发现，尽管三种ApoE变体的序列相似性极高，但仅ApoE4在分子动力学模拟（molecular dynamics simulations）中展现出以亚型特异性域间相互作用为特征的错误折叠中间态。ApoE4特异性错误折叠中间态的存在，可通过改变参与ApoE依赖性脂质转运效率、或AD相关蛋白聚集与清除的多条细胞通路，进而促成AD发病。本研究报道了我们认为的首个ApoE4错误折叠中间态的结构模型，该模型或可阐明ApoE4在AD发病机制中的分子作用机理。对ApoE4折叠中间态结构的解析，可为开发靶向对抗AD的合理化治疗策略提供全新的研究平台。