amyloid-beta-peptides and nimesulide

Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer's disease (AD). We determined the impact of two nonsteroidal anti-inflammatory drugs on A beta levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced A beta(1-40) and A beta(1-42) levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-kappa B activity. By contrast, nimesulide had no effect on both A beta peptides and NF-kappa B. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of A beta peptides or the A beta precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti-amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-kappa B significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cerebellar Cortex; Cyclooxygenase 1; Cyclooxygenase 2; Female; Glial Fibrillary Acidic Protein; Hippocampus; Indomethacin; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Transgenic; Models, Animal; NF-kappa B; NIH 3T3 Cells; Peptide Fragments; Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Sulfonamides