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<p>The ε4 allele of the Apolipoprotein E (<i>APOE</i>) 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 <i>N</i>-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, in an APOE4 &gt; 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 <i>APOE</i> polymorphism contributes to the risk for neurodegenerative diseases, and provides a theoretical basis for the future APOE targeted treatment of neurological diseases.</p>

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APOE4 triggers dysregulated synaptic vesicle release by disrupting SNARE complex assembly

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月23日

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  • Feng Chen,
  • Yanting Chen,
  • Sifan Feng,
  • Huiyi Chen,
  • Liehua Deng,
  • Fubin Ma,
  • Qiongwei Ke,
  • Qiuhao Liang,
  • Ji Chen,
  • Xiaoping Peng,
  • Jiongtong Lu,
  • Yingxuan Liu,
  • Yuying Xie,
  • Hao Cao,
  • Yuanhong Sun,
  • Wenxian Wu,
  • Lili Cui,
  • Yan Wang

摘要

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.