Inhibition of PC12 cell redox activity is a specific, early indicator of the mechanism of beta-amyloid-mediated cell death.
An in vitro tissue culture cell model system for investigating the biochemical mechanisms involved in the neurodegenerative actions of beta-amyloid has been established. Using rat pheochromocytoma PC12 cells, it was found that an early, specific response of cells to the beta-amyloid protein or the beta-amyloid fragment 25-35 was a potent inhibition of cellular redox activity, as measured by 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) reduction. This inhibitory response was rapid and occurred at nanomolar concentrations of peptide, concentrations at which no equivalent decreases in cell proliferation or cell survival were observed. The inhibition of PC12 cell MTT reduction was initially reversible upon removal of the peptide; if sustained for several days, however, by repeated peptide application, it became associated with a dramatic reduction in cell survival. Inhibition of MTT reduction may, therefore, be an early indicator of the mechanism of beta-amyloid-mediated cell death.
Shearman
M S
MS
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom.
Ragan
C I
CI
Iversen
L L
LL
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D013778:Tetrazolium Salts; D013844:Thiazoles; D009243:NAD; D009249:NADP; C022616:thiazolyl blue