The Alzheimer's disease genetic risk factor BIN1 induces isoform-dependent neurotoxicity through early endosome defects

The Bridging Integrator 1 (BIN1) gene is a major genetic risk factor for Alzheimers disease (AD) but little is known about its physiological functions. In addition, deciphering its potential pathophysiological role is difficult due to its numerous isoforms expressed in different cerebral cell types. Here we took advantage of a drosophila model to assess in vivo the impact of different BIN1 isoforms on neuronal toxicity: the neuronal isoform 1 (BIN1iso1), the muscular isoform 8 (BIN1iso8) and the ubiquituous isoform 9 (BIN1iso9). We showed that contrary to BIN1iso8 and BIN1iso9, BIN1iso1 overexpression induced neurodegeneration and an accumulation of vesicles mainly labeled by endosome markers. Systematic search for endosome trafficking regulators that are able to rescue BIN1iso1-induced neurodegeneration indicated a defect in the early endosome trafficking machinery. In human induced neurons and cerebral organoids, BIN1 knock-out resulted in narrowing of the early endosomes. This phenotype was rescued by BIN1iso1 expression but not that of BIN1iso9. Finally, in accordance with our previous observation in flies, we also observed that BIN1iso1 overexpression led to an increase in size of the early endosomes in human induced neurons. Altogether, our data demonstrate that the AD genetic risk factor BIN1, and especially BIN1iso1, contributes to early-endosome size deregulation which is a very early pathophysiological feature observed in AD pathogenesis.