Abstract
Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising compounds increase Abeta42 levels in the brains of mice. The elevations in Abeta42 by these compounds are comparable to the increases in Abeta42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Abeta42 production in humans.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alzheimer Disease / metabolism*
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / biosynthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Aspartic Acid Endopeptidases
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Brain / metabolism*
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Celecoxib
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Cell Line
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Endopeptidases / metabolism*
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Enzyme Activation / drug effects
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Enzyme-Linked Immunosorbent Assay
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Female
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Fenofibrate / chemistry
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Fenofibrate / pharmacology
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Humans
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Hypolipidemic Agents / chemistry
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Hypolipidemic Agents / pharmacology
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins
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Mass Spectrometry
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Transfection
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rho-Associated Kinases
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rhoA GTP-Binding Protein / metabolism
Substances
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Amyloid beta-Peptides
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase Inhibitors
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Hypolipidemic Agents
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Intracellular Signaling Peptides and Proteins
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Pyrazoles
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Sulfonamides
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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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rhoA GTP-Binding Protein
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Celecoxib
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Fenofibrate