The amyloid precursor protein protects PC12 cells against endoplasmic reticulum stress-induced apoptosis

Endoplasmic reticulum (ER) stress is believed to play an important role in neurodegenerative disorders such as Alzheimer's disease. In the present study, we investigated the effect of the human amyloid precursor protein (APP) on the ER stress response in PC12 cells. Tunicamycin, an inhibitor of N-glycosylation, rapidly induced the expression of the ER-resident chaperone Bip/grp78, a known target gene of the unfolded protein response. Prolonged treatment with tunicamycin (greater than or equal to 12 h) resulted in the activation of executioner caspases 3 and 7. Interestingly, PC12 cells overexpressing human wild-type APP (APPwt) showed increased resistance to tunicamycin-induced apoptosis compared with empty vector-transfected controls. This neuroprotective effect was significantly diminished in cells expressing the Swedish mutation of APP (KM670/671NL). Similar effects were observed when ER stress was induced with brefeldin A, an inhibitor of ER-to-Golgi protein translocation. Of note, APP-mediated neuroprotection was not associated with altered expression of Bip/grp78 or transcription factor C/EBP homologous protein-10 (CHOP/GADD153), suggesting that APP acted either downstream or independently of ER-to-nucleus signaling. Our data indicate that APP plays an important physiological role in protecting neurons from the consequences of prolonged ER stress, and that APP mutations associated with familial Alzheimer's disease may impair this protective activity.