Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease

Am J Pathol. 2004 Dec;165(6):2197-206. doi: 10.1016/s0002-9440(10)63269-5.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cerebellar Cortex / metabolism
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / metabolism
  • Indomethacin / therapeutic use*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NIH 3T3 Cells / drug effects
  • NIH 3T3 Cells / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sulfonamides / administration & dosage

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Anti-Inflammatory Agents, Non-Steroidal
  • Glial Fibrillary Acidic Protein
  • Isoenzymes
  • Membrane Proteins
  • NF-kappa B
  • Peptide Fragments
  • RNA, Messenger
  • Sulfonamides
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • nimesulide
  • Indomethacin