A. Eckert et al., Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation, J NEUROSC R, 64(2), 2001, pp. 183-192
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.