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
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Amides / pharmacology
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / metabolism*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Aspartic Acid Endopeptidases
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Brain / drug effects
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Brain / metabolism
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Cell Line, Tumor
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Endopeptidases / metabolism
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Enzyme Inhibitors / pharmacology
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Guanosine Triphosphate / metabolism
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Humans
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Ibuprofen / pharmacology
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Intracellular Signaling Peptides and Proteins
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Mice
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Mice, Transgenic
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Peptide Fragments / metabolism*
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Polyisoprenyl Phosphates / pharmacology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Pyridines / pharmacology
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Sesquiterpenes
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Signal Transduction
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Sulindac / analogs & derivatives*
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Sulindac / pharmacology
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Transfection
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rho GTP-Binding Proteins / antagonists & inhibitors*
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rho GTP-Binding Proteins / metabolism
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rho-Associated Kinases
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rhoA GTP-Binding Protein / genetics
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rhoA GTP-Binding Protein / metabolism
Substances
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Amides
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Amyloid beta-Peptides
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Anti-Inflammatory Agents, Non-Steroidal
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Peptide Fragments
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Polyisoprenyl Phosphates
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Pyridines
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Sesquiterpenes
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amyloid beta-protein (1-38)
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amyloid beta-protein (1-42)
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Y 27632
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Sulindac
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sulindac sulfide
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farnesyl pyrophosphate
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Guanosine Triphosphate
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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geranylgeranyl pyrophosphate
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Ibuprofen