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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

Weggen, Sascha and Eriksen, Jason L. and Das, Pritam and Sagi, Sarah A. and Wang, Rong and Pietrzik, Claus U. and Findlay, Kirk A. and Smith, Tawnya E. and Murphy, Michael P. and Bulter, Thomas and Kang, David E. and Marquez-Sterling, Numa and Golde, Todd E. and Koo, Edward H. (2001) A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature, 414 (6860). pp. 212-216. ISSN 0028-0836. https://resolver.caltech.edu/CaltechAUTHORS:20150331-085540470

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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 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 NSAIDs. 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.


Item Type:Article
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http://dx.doi.org/10.1038/35102591DOIArticle
http://www.nature.com/nature/journal/v414/n6860/abs/414212a0.htmlPublisherArticle
http://www.nature.com/nature/journal/v414/n6860/suppinfo/414212a0.htmlRelated ItemSupplementary Information
http://rdcu.be/crq1PublisherFree ReadCube access
Additional Information:© 2001 Macmillan Magazines Ltd. Received 19 July 2001; Accepted 13 September 2001. 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.).
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
Beeson AwardUNSPECIFIED
Ellison Medical Foundation New Scholar AwardUNSPECIFIED
Robert and Clarice Smith FellowshipUNSPECIFIED
John Douglas French Alzheimer's Foundation FellowshipUNSPECIFIED
Deutsche Forschungsgemeinschaft Emmy Noether fellowshipUNSPECIFIED
Issue or Number:6860
Record Number:CaltechAUTHORS:20150331-085540470
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150331-085540470
Official Citation:A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity p212 Sascha Weggen, Jason L. Eriksen, Pritam Das, Sarah A. Sagi, Rong Wang, Claus U. Pietrzik, Kirk A. Findlay, Tawnya E. Smith, Michael P. Murphy, Thomas Bulter, David E. Kang, Numa Marquez-Sterling, Todd E. Golde and Edward H. Koo doi:10.1038/35102591
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:56233
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:31 Mar 2015 17:14
Last Modified:03 Oct 2019 08:12

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