Sulphated compounds attenuate beta-amyloid toxicity by inhibiting its association with cells.
Agents that interfere with the toxic effects of beta-amyloid protein may be therapeutically useful against Alzheimer's disease. We reported recently that several sulphated glycosaminoglycans and sulphonated dyes attenuate the toxic effects of beta-amyloid fragments beta 25-35 and beta 1-40 in two clonal cell lines. We now demonstrate that this protective effect is due to interference with beta-amyloid cell association rather than effects on beta-amyloid structure. Using an enzyme-linked immunoabsorbance assay to detect cell-associated beta 1-40, we found in a range of compounds a strong correlation between inhibition of HeLa cell association of beta 1-40 and attenuation of cellular toxicity as measured by inhibition of 3-[4,5-dimethylthia-zol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction. In contrast, effects on peptide structure, as measured by Congo red binding, were generally inconsistent with the attenuating effects of the compounds on cellular toxicity. These results suggest that by binding beta-amyloid these agents prevent its interaction with cells.
Sadler
I I
II
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Smith
D W
DW
Shearman
M S
MS
Ragan
C I
CI
Tailor
V J
VJ
Pollack
S J
SJ
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004396:Coloring Agents; D003224:Congo Red; D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013431:Sulfates / Q000494:pharmacology*; D013451:Sulfonic Acids / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D013431:Sulfates; D013451:Sulfonic Acids; D013778:Tetrazolium Salts; D013844:Thiazoles; D003224:Congo Red; C022616:thiazolyl blue