title: Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production.
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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kukar
authors.forename: Michael Paul
authors.initials: MP
authors.lastname: Murphy
authors.forename: Jason L
authors.initials: JL
authors.lastname: Eriksen
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sagi
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.forename: Tawnya E
authors.initials: TE
authors.lastname: Smith
authors.forename: Thomas
authors.initials: T
authors.lastname: Ladd
authors.forename: Murad A
authors.initials: MA
authors.lastname: Khan
authors.forename: Rajashaker
authors.initials: R
authors.lastname: Kache
authors.forename: Jenny
authors.initials: J
authors.lastname: Beard
authors.forename: Mark
authors.initials: M
authors.lastname: Dodson
authors.forename: Sami
authors.initials: S
authors.lastname: Merit
authors.forename: Victor V
authors.initials: VV
authors.lastname: Ozols
authors.forename: Panos Z
authors.initials: PZ
authors.lastname: Anastasiadis
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.forename: Abdul
authors.initials: A
authors.lastname: Fauq
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism*; D000068579:Celecoxib; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D011345:Fenofibrate / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D013058:Mass Spectrometry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D000960:Hypolipidemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D020742:rhoA GTP-Binding Protein; D000068579:Celecoxib; D011345:Fenofibrate