title: Overexpression of amyloid-β protein precursor induces mitochondrial oxidative stress and activates the intrinsic apoptotic cascade.
abstract: Aberrant processing of amyloid-β protein precursor (AβPP) into amyloid-β (Aβ) fragments underlies the formation of senile plaques in Alzheimer's disease (AD). Moreover, Aβ fragments, particularly Aβ(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) AβPP protein, due to its location on chromosome 21. However, the mechanism by which the overexpression of WT AβPP might trigger MOS and induce cell death is presently unclear. Here we show that transient overexpression of DsRed2-tagged AβPP (WT) in CHO cells induces caspase-3 activation and nuclear fragmentation indicative of apoptosis. AβPP 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 AβPP 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 AβPP-induced apoptosis. AβPP-induced apoptosis is unaffected by a β-secretase inhibitor and is independent of detectable Aβ(42); however, a γ-secretase inhibitor significantly protects against AβPP overexpression, suggesting a possible role of the AβPP intracellular domain in cell death. These data indicate that overexpression of WT AβPP is sufficient to induce MOS and intrinsic apoptosis, suggesting a novel pro-oxidant role for AβPP at mitochondria which may be relevant in AD and DS disease pathologies.
authors: Department of Biological Sciences and the Eleanor Roosevelt Institute, University of Denver, Denver, CO, USA.
authors: Matthew G
authors: MG
authors: Bartley
authors: Kristin
authors: K
authors: Marquardt
authors: Danielle
authors: D
authors: Kirchhof
authors: Heather M
authors: HM
authors: Wilkins
authors: David
authors: D
authors: Patterson
authors: Daniel A
authors: DA
authors: Linseman
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D016564:Amyloid beta-Protein Precursor