Onyango IG, Bennett JP Jr, Tuttle JB.

Center for the Study of Neurodegenerative Diseases, University of
Virginia School of Medicine, Charlottesville, VA 22908, USA; Department
of Neuroscience, University of Virginia, MR4 Building Room 6148, 300
Park Place, PO Box 801392, Charlottesville, VA 22908, USA; Department
of Neurology, University of Virginia School of Medicine,
Charlottesville, VA 22908, USA.

Although oxidative stress and mitochondrial dysfunction have been
linked to neurodegenerative diseases such as Alzheimer's disease (AD),
it is not fully understood how mitochondrial oxidative stress may
induce neuronal death. We used mitochondrial transgenic neuronal cell
cybrid models of sporadic AD (SAD) to investigate the effects of
endogenously generated reactive oxygen species (ROS) on viability and
cell death mechanisms. Compared to control (CTL) cybrids, SAD cybrids
have increased accumulation of oxidative stress markers and increased
apoptosis that is blocked by N-acetylcysteine (NAC) and zVAD.fmk. SAD
cybrids also have increased basal activation of the MAPKs, Akt, and
NF-kappaB. NF-kappaB activation and cybrid viability are enhanced by
NAC. Inhibiting the activity of the PI3K pathway or NF-kappaB
aggravates neuronal death. Exposure of CTL cybrids to H(2)O(2)
decreased viability and activated in a NAC-sensitive manner, the same
intracellular signaling pathways active under basal conditions in SAD
cybrids.