NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo.
Epidemiologic studies demonstrate that long-term use of NSAIDs is associated with a reduced risk for the development of Alzheimer disease (AD). In this study, 20 commonly used NSAIDs, dapsone, and enantiomers of flurbiprofen were analyzed for their ability to lower the level of the 42-amino-acid form of amyloid beta protein (Abeta42) in a human H4 cell line. Thirteen of the NSAIDs and the enantiomers of flurbiprofen were then tested in acute dosing studies in amyloid beta protein precursor (APP) transgenic mice, and plasma and brain levels of Abeta and the drug were evaluated. These studies show that (a). eight FDA-approved NSAIDs lower Abeta42 in vivo, (b). the ability of an NSAID to lower Abeta42 levels in cell culture is highly predicative of its in vivo activity, (c). in vivo Abeta42 lowering in mice occurs at drug levels achievable in humans, and (d). there is a significant correlation between Abeta42 lowering and levels of ibuprofen. Importantly, flurbiprofen and its enantiomers selectively lower Abeta42 levels in broken cell gamma-secretase assays, indicating that these compounds directly target the gamma-secretase complex that generates Abeta from APP. Of the compounds tested, meclofenamic acid, racemic flurbiprofen, and the purified R and S enantiomers of flurbiprofen lowered Abeta42 levels to the greatest extent. Because R-flurbiprofen reduces Abeta42 levels by targeting gamma-secretase and has reduced side effects related to inhibition of cyclooxygenase (COX), it is an excellent candidate for clinical testing as an Abeta42 lowering agent.
Eriksen
Jason L
JL
Department of Neuroscience, Mayo Graduate School, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA.
Sagi
Sarah A
SA
Smith
Tawnya E
TE
Weggen
Sascha
S
Das
Pritam
P
McLendon
D C
DC
Ozols
Victor V
VV
Jessing
Kevin W
KW
Zavitz
Kenton H
KH
Koo
Edward H
EH
Golde
Todd E
TE
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D005260:Female; D005480:Flurbiprofen / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008469:Meclofenamic Acid / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D011480:Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; D011480:Protease Inhibitors; C075222:amyloid beta-protein (1-42); D008469:Meclofenamic Acid; D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse