Neurodegenerative mechanisms in Alzheimer disease. A role for oxidative damage in amyloid beta protein precursor-mediated cell death.
We have established a stably transformed human neuroblastoma cell line (MC65) that conditionally expresses a C-terminal derivative of the amyloid beta protein precursor (beta PP) termed S beta C (a fusion protein composed of the amino-17 and carboxyl-99 residues of beta PP). Conditional expression of S beta C (mediated by the withdrawal of tetracycline from the culture medium) induces pronounced nuclear DNA fragmentation and cytotoxicity in this cell line. These effects are enhanced by hyperoxygen and suppressed by hypooxygen and antioxidants. This cell line is relatively insensitive to the extracellular application of amyloid beta 25-35, and coculture experiments suggest that this cytotoxicity is mediated by an intracellular process. These findings suggest that the overexpression of the C-terminal domain of beta PP can disrupt normal cellular processes in these cells in such a way as to induce a directed (deoxyribonuclease-mediated) mechanism of cell death. This process appears to be modulated and/or mediated by a reactive oxygen specie(s) (ROS). Consistent with a role for ROS in the process of S beta C-mediated toxicity, we have found that the MC65 cell line is hypersensitive to oxidative stress and that it is this sensitivity that appears (at least in part) to underlie its susceptibility to S beta C.
Sopher
B L
BL
Department of Pathology, University of Washington, Seattle 98195-7470, USA.
Fukuchi
K
K
Kavanagh
T J
TJ
Furlong
C E
CE
Martin
G M
GM
D000111:Acetylcysteine / Q000494:pharmacology; D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000502:physiology*; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D006801:Humans; D008855:Microscopy, Electron, Scanning; D009447:Neuroblastoma; D018384:Oxidative Stress; D011761:Pyrrolidonecarboxylic Acid; D017382:Reactive Oxygen Species / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013752:Tetracycline / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D008063:Thioctic Acid / Q000494:pharmacology; D014162:Transfection; D014810:Vitamin E / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D004273:DNA, Neoplasm; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D053778:Thiazolidines; D014810:Vitamin E; D008063:Thioctic Acid; D013752:Tetracycline; D011761:Pyrrolidonecarboxylic Acid; D000111:Acetylcysteine; C029536:2-oxothiazolidine-4-carboxylic acid