Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production.
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.
Kukar
Thomas
T
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA.
Murphy
Michael Paul
MP
Eriksen
Jason L
JL
Sagi
Sarah A
SA
Weggen
Sascha
S
Smith
Tawnya E
TE
Ladd
Thomas
T
Khan
Murad A
MA
Kache
Rajashaker
R
Beard
Jenny
J
Dodson
Mark
M
Merit
Sami
S
Ozols
Victor V
VV
Anastasiadis
Panos Z
PZ
Das
Pritam
P
Fauq
Abdul
A
Koo
Edward H
EH
Golde
Todd E
TE
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
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