Chen Feng, Chen Yanting, Feng Sifan, Chen Huiyi, Deng Liehua, Ma Fubin, Ke Qiongwei, Liang Qiuhao, Chen Ji, Peng Xiaoping, Lu Jiongtong, Liu Yingxuan, Xie Yuying, Cao Hao, Sun Yuanhong, Wu Wenxian, Cui Lili, Wang Yan
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, China.
The Marine Biomedical Research Institute of Guangdong, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, 524023, China.
Cell Mol Life Sci. 2025 Jun 23;82(1):248. doi: 10.1007/s00018-025-05787-6.
The ε4 allele of the Apolipoprotein E (APOE) gene is an important genetic risk factor for several neurodegenerative diseases, while the common pathogenic mechanism is still unclear. Impaired synaptic transmission is one of the common pathogenic features of neurodegenerative diseases. By using proteomics analysis, co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assay, we demonstrated that APOE interacts with VAMP2, a core component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, in an APOE4 > APOE3 manner. Further in vitro and in vivo results suggest that APOE4 blocks SNARE complex assembly, which is likely driven by liquid-liquid phase separation (LLPS), negatively regulating synaptic vesicle release. Our study shows that APOE4 negatively regulates synaptic vesicle release by blocking the soluble SNARE complex assembly. Our data shed a light on how APOE polymorphism contributes to the risk for neurodegenerative diseases, and provides a theoretical basis for the future APOE targeted treatment of neurological diseases.
载脂蛋白E（APOE）基因的ε4等位基因是几种神经退行性疾病的重要遗传风险因素，但其常见致病机制仍不清楚。突触传递受损是神经退行性疾病的常见致病特征之一。通过蛋白质组学分析、免疫共沉淀（Co-IP）和双分子荧光互补（BiFC）试验，我们证明APOE以APOE4>APOE3的方式与可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合体的核心成分VAMP2相互作用。进一步的体外和体内结果表明，APOE4阻断SNARE复合体组装，这可能由液-液相分离（LLPS）驱动，对突触小泡释放产生负调节作用。我们的研究表明，APOE4通过阻断可溶性SNARE复合体组装对突触小泡释放产生负调节作用。我们的数据揭示了APOE多态性如何导致神经退行性疾病风险，并为未来针对APOE的神经疾病治疗提供了理论基础。
