Alzheimer's genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses.

ABSTRACT: BIN1, a late-onset Alzheimer's disease (LOAD) risk gene, is an endocytic regulator with an unclear synaptic function. We find Bin1 more prominently in inhibitory synapses (vGAT positive) than in excitatory ones (vGLUT1 positive). Bin1 knockdown reduces inhibitory synapses independently of Aβ42 production, increasing GABA release from the remaining synapses due to accelerated vGAT exocytosis and endocytosis, which decreases the size of inhibitory synaptic endosomes. In excitatory synapses, Bin1 only reduces vGLUT1 exocytosis. LOAD Bin1 mutants cannot compensate for the loss of inhibitory synapses, suggesting that these mutations are pathogenic. A loss of Bin1 function increases neuronal calcium levels and hyperexcitability, leading to elevated glutamate release due to lack of inhibition. Le

SUBMITTER: Barata MA 

PROVIDER: S-EPMC12381520 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature