Amyloid-beta induces distinct forms of cell death in different neuronal populations

Recent FDA approval for treating Alzheimer’s disease (AD) with amyloid-beta (Aβ) immunotherapy is a historic breakthrough, which has rekindled widespread interest in understanding the molecular basis of Aβ toxicity. In this study, we developed a novel Drosophila model to investigate Aβ42-induced pathologies in vivo and in real time. Strikingly, we unveiled compelling evidence that secreted Aβ42 affects different neurons in distinct ways—both in susceptibility to Aβ42 deposition and in the mode of cell death triggered. Additionally, we observed altered larval crawling behaviour which—remarkably—could be recovered by inhibiting ferroptotic cell death with small molecule inhibitors. Collectively these findings showcase this as a powerful new model for investigating Aβ toxicity in AD and identifying novel treatment strategies