farnesyl-pyrophosphate and sulindac-sulfide

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.

Topics: Amides; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartic Acid Endopeptidases; Brain; Cell Line, Tumor; Endopeptidases; Enzyme Inhibitors; Guanosine Triphosphate; Humans; Ibuprofen; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Peptide Fragments; Polyisoprenyl Phosphates; Protein Serine-Threonine Kinases; Pyridines; rho GTP-Binding Proteins; rho-Associated Kinases; rhoA GTP-Binding Protein; Sesquiterpenes; Signal Transduction; Sulindac; Transfection