Carboxyl-terminal fragment of amyloid precursor protein and hydrogen peroxide induce neuronal cell death through different pathways.
Carboxyl-terminal fragments (CTs) of the amyloid precursor protein have been shown to be highly neurotoxic and are though to contribute to the neuropathology of Alzheimer's disease. We compared the effects of expressing CT99 in the human neuroblastoma MC65 with the effects of hydrogen peroxide on the parental SK-N-MC cells. CT99 and hydrogen peroxide generated a different pattern of free radicals and their toxic effects were differentially protected by a battery of antioxidants. Hydrogen peroxide caused a cell cycle arrest at phase S and apoptosis mediated through caspase-3 activation in a pattern similar to that described for amyloid-beta neurotoxicity. However, CT99 apoptosis appeared to be mediated through an unidentified mitochondrial pathway. Both oxidative injury types induced heme oxygenase-1 expression as a neuroprotective response. Overall we found a coincidence in the nonespecific stress oxidative effects of CT99 and hydrogen peroxide, but clear differences on their respective potencies and pathways of neurotoxicity.
Sebastià
J
J
Department of Pharmacology and Toxicology, IIBB, CSIC-IDIBAPS, Barcelona, Spain.
Pertusa
M
M
Vílchez
D
D
Planas
A M
AM
Verbeek
R
R
Rodríguez-Farré
E
E
Cristòfol
R
R
Sanfeliu
C
C
D016564:Amyloid beta-Protein Precursor / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects*; D013050:Spectrometry, Fluorescence; D013481:Superoxides / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D013481:Superoxides; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D053148:Caspase 3