Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Abeta42 by inhibiting Rho

Science. 2003 Nov 14;302(5648):1215-7. doi: 10.1126/science.1090154.

Abstract

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity.

MeSH terms

  • Amides / pharmacology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Aspartic Acid Endopeptidases
  • Brain / drug effects
  • Brain / metabolism
  • Cell Line, Tumor
  • Endopeptidases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Guanosine Triphosphate / metabolism
  • Humans
  • Ibuprofen / pharmacology
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / metabolism*
  • Polyisoprenyl Phosphates / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Pyridines / pharmacology
  • Sesquiterpenes
  • Signal Transduction
  • Sulindac / analogs & derivatives*
  • Sulindac / pharmacology
  • Transfection
  • rho GTP-Binding Proteins / antagonists & inhibitors*
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Amides
  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Peptide Fragments
  • Polyisoprenyl Phosphates
  • Pyridines
  • Sesquiterpenes
  • amyloid beta-protein (1-38)
  • amyloid beta-protein (1-42)
  • Y 27632
  • Sulindac
  • sulindac sulfide
  • farnesyl pyrophosphate
  • Guanosine Triphosphate
  • Protein Serine-Threonine Kinases
  • rho-Associated Kinases
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • geranylgeranyl pyrophosphate
  • Ibuprofen