Cytosolic amyloid-β peptide 42 escaping from degradation induces cell death

Accumulating evidence suggests that intracellular amyloid-β (Aβ) peptide triggers the early pathological events in Alzheimer’s disease (AD). However, little is known about the consequence of cytosolic Aβ. In this study, we ectopically expressed Aβ42 in the cytoplasm of SH-SY5Y neuroblastoma cells by expressing a fusion protein of GFP-tagged ubiquitin and Aβ42 (GFPUb-Aβ42). Although GFPUb and Aβ42 are stochastically produced with the same molar ratio in the cytoplasm, Aβ42 was completely degraded in more than 50% of the GFPUb-expressing cells. However, if Aβ42 was not degraded in their cytoplasm, then Aβ42-expressing cells underwent apoptosis. The number of Aβ42-expressing cells is significantly increased by the inhibition of proteasome with MG132. Cytosolic Aβ42 which has escaped degradation inhibits proteasome and thereby may accelerate the accumulation of Aβ42 and its detrimental effects. Our findings suggest that cells have the potential to degrade Aβ42 in their cytoplasm but if Aβ42 appears in the cytoplasm due to its incomplete degradation, it accumulates and may trigger the fatal cascade of pathology of AD.