Beta-amyloid-induced cell toxicity: enhancement of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-dependent cell death.
In an attempt to understand the cause of neurodegeneration in Alzheimer's disease, the toxic effects of beta-amyloid (Abeta) peptides have been widely studied. At high micromolar concentrations Abeta peptides have been demonstrated to be acutely toxic to various cell types. At submicromolar concentrations, Abeta peptides have been suggested to inhibit cellular metabolic activity, due to their inhibition of the ability of cells to metabolize the oxidoreductase substrate 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Here we show, first, that MTT reduction surprisingly leads to a breakdown in PC12 cell membrane integrity and cell death, presumably through the formation of a crystalline formazan product, and, second, that pretreatment of PC12 cells with nanomolar concentrations of Abeta peptide, rather than inhibiting their metabolic activity, increases the susceptibility of these cells to the secondary toxic effect of formazan crystal formation. These results suggest that low nanomolar concentrations of Abeta render membranes more susceptible to damage by a secondary insult, in this case, MTT reduction. It is plausible that such an effect, when combined with additional risk factors, could contribute to the neurodegeneration that occurs in Alzheimer's disease.
Hertel
C
C
Preclinical Research, Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Hauser
N
N
Schubenel
R
R
Seilheimer
B
B
Kemp
J A
JA
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D007700:Kinetics; D009498:Neurotoxins / Q000494:pharmacology; D016716:PC12 Cells / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D012680:Sensitivity and Specificity; D013778:Tetrazolium Salts / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue