APOE4 triggers dysregulated synaptic vesicle release by disrupting SNARE complex assembly

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Apolipoprotein E (APOE) ε4 allele is a significant genetic risk factor for neurodegenerative diseases.
• Impaired synaptic transmission is a common pathological feature in these conditions.

Purpose of the Study:

• To elucidate the pathogenic mechanism linking APOE ε4 to neurodegeneration.
• To investigate the interaction between APOE and synaptic vesicle release machinery.

Main Methods:

• Proteomics analysis
• Co-immunoprecipitation (Co-IP)
• Bimolecular fluorescence complementation (BiFC) assay
• In vitro and in vivo studies

Main Results:

• APOE interacts with VAMP2, a key component of the SNARE complex, with higher affinity in the APOE4 variant compared to APOE3.
• APOE4 inhibits SNARE complex assembly, potentially through liquid-liquid phase separation (LLPS).
• This inhibition negatively regulates synaptic vesicle release.

Conclusions:

• APOE4 disrupts synaptic vesicle release by impeding SNARE complex formation.
• This mechanism provides insight into APOE's role in neurodegenerative disease pathogenesis.
• Findings offer a theoretical basis for developing APOE-targeted neurological disease treatments.