title: A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity.
abstract: Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide (the 42-residue isoform of the amyloid-beta peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant beta-amyloid precursor protein (APP) lowered their brain levels of Abeta42. In cultured cells, the decrease in Abeta42 secretion was accompanied by an increase in the Abeta(1-38) isoform, indicating that NSAIDs subtly alter gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Abeta42 peptide levels independently of COX activity and that this Abeta42-lowering activity could be optimized to selectively target the pathogenic Abeta42 species.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: S
authors.initials: S
authors.lastname: Weggen
authors.forename: J L
authors.initials: JL
authors.lastname: Eriksen
authors.forename: P
authors.initials: P
authors.lastname: Das
authors.forename: S A
authors.initials: SA
authors.lastname: Sagi
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: C U
authors.initials: CU
authors.lastname: Pietrzik
authors.forename: K A
authors.initials: KA
authors.lastname: Findlay
authors.forename: T E
authors.initials: TE
authors.lastname: Smith
authors.forename: M P
authors.initials: MP
authors.lastname: Murphy
authors.forename: T
authors.initials: T
authors.lastname: Bulter
authors.forename: D E
authors.initials: DE
authors.lastname: Kang
authors.forename: N
authors.initials: N
authors.lastname: Marquez-Sterling
authors.forename: T E
authors.initials: TE
authors.lastname: Golde
authors.forename: E H
authors.initials: EH
authors.lastname: Koo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013467:Sulindac; C025462:sulindac sulfide; D011451:Prostaglandin-Endoperoxide Synthases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D007052:Ibuprofen; D007213:Indomethacin