Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation

The Swedish double mutation (KM670/671NL) of amyloid precursor protein (APP sw) is associated with early-onset familiar Alzheimer's disease (FAD) and r esults in from three- to sixfold increased beta -amyloid production. The go al of the present study was to elucidate the effects of APPsw on mechanisms of apoptotic cell death. Therefore, PC12 cells were stably transfected wit h human APPsw. Here we report that the vulnerability of APPsw-bearing PC12 cells to undergo apoptotic cell death was significantly enhanced after expo sure to hydrogen peroxide compared to human wild-type APP-bearing cells, em pty vector-transfected cells, and parent untransfected cells. In addition, we have analyzed the potential influence of several mechanisms that can int erfere with the execution of the apoptotic cell death program: the inhibiti on of cell death by the use of caspase inhibitors and the reduction of oxid ative stress by the use of (+/-)-alpha -tocopherol (vitamin E). Interesting ly, oxidative stress-induced cell death was significantly attenuated in APP sw PC12 cells by pretreatment with caspase-3 inhibitors but not with caspas e-1 inhibitors. In parallel, caspase-3 activity was markedly elevated in AP Psw PC12 after stimulation with hydrogen peroxide for 6 hr, whereas caspase -1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (+/-)-alpha -tocop herol. The protective potency of (+/-)-alpha -tocopherol was even greater t han that of caspase-3 inhibitors. Our findings further emphasize the role o f mutations in the amyloid precursor protein in apoptotic cell death and ma y provide the fundamental basis for further efforts to elucidate the underl ying processes caused by FAD-related mutations. J. Neurosci. Res. 64:183-19 2, 2001. (C) 2001 Wiley-Liss, Inc.