Overexpression of Amyloid-β Protein Precursor Induces Mitochondrial Oxidative Stress and Activates the Intrinsic Apoptotic Cascade

Aberrant processing of amyloid-beta protein precursor (A beta PP) into amyloid-beta (A beta) fragments underlies the formation of senile plaques in Alzheimer's disease (AD). Moreover, A beta fragments, particularly A beta(42), exert direct toxic effects within neurons including the induction of mitochondrial oxidative stress (MOS). Interestingly, individuals with Down syndrome (DS) frequently develop early onset AD as a major co-morbid phenotype. One hypothesis for AD associated with DS involves the overexpression of wild type (WT) A beta PP protein, due to its location on chromosome 21. However, the mechanism by which the overexpression of WT A beta PP might trigger MOS and induce cell death is presently unclear. Here we show that transient overexpression of DsRed2-tagged A beta PP (WT) in CHO cells induces caspase-3 activation and nuclear fragmentation indicative of apoptosis. A beta PP localizes to the mitochondrial fraction of transfected CHO cells and induces glutathione- sensitive opening of the mitochondrial permeability transition pore (mPTP) and cytochrome c release. MOS and intrinsic apoptosis induced by A beta PP are significantly inhibited by co-expression of Bcl-2 or treatment with either glutathione or a pan-caspase inhibitor. The mPTP inhibitor, cyclosporin A, also significantly attenuates A beta PP-induced apoptosis. A beta PP-induced apoptosis is unaffected by a beta-secretase inhibitor and is independent of detectable A beta(42); however, a gamma-secretase inhibitor significantly protects against A beta PP overexpression, suggesting a possible role of the A beta PP intracellular domain in cell death. These data indicate that overexpression of WT A beta PP is sufficient to induce MOS and intrinsic apoptosis, suggesting a novel pro-oxidant role for A beta PP at mitochondria which may be relevant in AD and DS disease pathologies.