Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs)1,2,3,4,5. 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 Aβ42 peptide (the 42-residue isoform of the amyloid-β 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 NSAIDs6. Furthermore, short-term administration of ibuprofen to mice that produce mutant β-amyloid precursor protein (APP) lowered their brain levels of Aβ42. In cultured cells, the decrease in Aβ42 secretion was accompanied by an increase in the Aβ(1–38) isoform, indicating that NSAIDs subtly alter γ-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 Aβ42 peptide levels independently of COX activity and that this Aβ42-lowering activity could be optimized to selectively target the pathogenic Aβ42 species.
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We thank X. Zhang and D. A. Young for fibroblasts deficient in COX-1 and COX-2; R. Kopan for Notch plasmids; M. Kounnas for 26D6 antibody; P. Sims, D. Galasko and C. Eckman for discussions; and Takeda industries for the BAN50, BA27 and BC05 antibodies. We also thank P. Needleman for his scientific input. This work was supported by National Institutes of Health grants (E.H.K., T.E.G., R.W.), a Beeson Award (T.E.G.), an Ellison Medical Foundation New Scholars award (T.E.G.), a Robert and Clarice Smith Fellowship (P.D.), a John Douglas French Alzheimer's Foundation Fellowship (M.P.M.), and an Emmy Noether fellowship from the Deutsche Forschungsgemeinschaft (S.W.).
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