Aβ promotes calpain mediated α-syn fragmentation and caspase-3 dependent cell death in α-syn-expressing neuronal cells. A. Diagrammatic representation of calpain-mediated α-syn cleavage resulting in C-terminus truncation of α-syn. B. Representative Western blot showing increased levels in both FL-α-syn (14 kDa) in the cytosolic (single band) and membrane (double band) fractions, as wells as an increase in C-terminus cleavage of α-syn (12 kDa) when cells were pre-treated with Aβ. C. Representative confocal microscopy and D image analysis of B103 neuroblastoma cells treated with combinations of LV-α-syn and/or Aβ oligomers revealed increased CT-α-syn-ir (* p < 0.05; one-way ANOVA and Dunnett’s post hoc analysis compared to LV-α-syn treated with vehicle). E. Increased β-spectrin degradation by calpain and caspase-3, in the presence of LV-α-syn and Aβ. F. Caspase-3 activity was increased in cells treated with Aβ alone and combined with LV-α-syn. * p < 0.05; one-way ANOVA and Dunnett’s post hoc analysis compared to uninfected, vehicle-treated control. G. Calpain and caspase inhibitors rescued cell death induced by combined toxicity of Aβ and LV-α-syn. H. Co-ip of α-syn and caspase-3 in the presence of Aβ.