A? induces endoplasmic reticulum stress causing possible proteasome impairment via the endoplasmic reticulum?associated degradation pathway

Background: Accumulation of β-amyloid is a major pathology of Alzheimer’s disease (AD). As in other neurodegenerative diseases, it is also reported that proteasome activity is deteriorated in post-mortem brains of AD patients. However, the mechanism of proteasomal dysfunction in AD remains unexplained. There is, however, increasing reported evidence that the unfolded protein response (UPR) is involved in AD pathology. Here we show that Aβ causes not only the UPR leading to endoplasmic reticulum (ER) stress mediated cell death, but also proteasomal dysfunction in cultured cells. Methods: Mouse primary cultured neurons and other cultured cells such as HEK 293T or SH-SY5Y were treated with Aβ or other reagents, such as thapsigargin and lactacystin, to study UPR or proteasome activity. The UPR was investigated using proteins or mRNA expression. To ascertain proteasome activity, we also recruited SH-SY5Y cells stably transfected with GFPu. Results: In vitro study showed that UPR, phosphorylation of eIF-2α and BiP degradation preceded proteasome dysfunction. It is known that the UPR of ER occurs with the assistance of proteasome as ER-associated protein degradation (ERAD). Conclusion: This evidence, taken together, suggests that Aβ may induce proteasome dysfunction by preceding the UPR through ER-associated protein degradation.