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BIN1 gain-of-function in the presynaptic compartment leads to isoform-specific synaptotoxicity
Erwan Lambert1, Carla Gelle1, Valentin Leclerc1
1Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID - AGE - Facteurs de risque et déterminants moléculaires liés au vieillissement, LabEx DISTALZ, Lille, France.
Alzheimer'S Research & Therapy
|June 4, 2026
Summary
The Alzheimer's disease (AD) gene BIN1 isoform 1 (BIN1iso1) causes synapse damage, particularly in presynaptic neurons. This BIN1iso1 synaptotoxicity may explain early synapse loss in AD, highlighting BIN1iso1 as a therapeutic target.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Alzheimer's disease (AD) is linked to genetic factors and early synaptic dysfunction.
- The BIN1 gene is a major AD susceptibility gene, but its specific role and isoform effects at synapses are not well understood.
Purpose of the Study:
- To investigate the impact of different human BIN1 isoforms on synaptic structure and function.
- To determine the presynaptic versus postsynaptic roles of BIN1 isoforms in synaptic integrity.
Main Methods:
- Overexpression of human BIN1 isoforms in Drosophila neurons (photoreceptors and motoneurons) and rat hippocampal neurons.
- Electrophysiology, ultrastructural analysis, and immunofluorescence to assess synaptic function and morphology.
- Utilized microfluidic devices for precise neuronal compartment targeting and microelectrode arrays for functional connectivity assessment.
Main Results:
- BIN1 isoform 1 (BIN1iso1) overexpression led to synaptotoxicity and synaptic transmission loss in Drosophila, linked to endosomal trafficking defects.
- BIN1iso1 altered synapse morphology in motoneurons and decreased synaptic connectivity in rat hippocampal neurons when expressed presynaptically.
- Rab11 modulation partially rescued BIN1iso1-induced synaptotoxicity in Drosophila, suggesting a role for endosomal trafficking.
Conclusions:
- BIN1iso1 causes isoform-specific, presynaptic disruption that compromises synaptic integrity across species.
- BIN1iso1 synaptotoxicity is a potential mechanism contributing to early synapse loss in Alzheimer's disease.
- BIN1iso1 represents a potential therapeutic target for preserving synaptic function in AD.
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