A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

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, Edward H. Koo

Research output: Contribution to journalArticle

1214 Citations (Scopus)

Abstract

Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs)1-5. 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.

Original languageEnglish (US)
Pages (from-to)212-216
Number of pages5
JournalNature
Volume414
Issue number6860
DOIs
StatePublished - Nov 8 2001

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Prostaglandin-Endoperoxide Synthases
Anti-Inflammatory Agents
Pharmaceutical Preparations
Amyloid beta-Protein Precursor
Ibuprofen
Amyloid
Cultured Cells
Protein Isoforms
Brain
Amyloid Precursor Protein Secretases
Indomethacin
Epidemiologic Studies
Alzheimer Disease
Pharmacology
Pathology
Peptides

ASJC Scopus subject areas

  • General

Cite this

Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., ... Koo, E. H. (2001). A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature, 414(6860), 212-216. https://doi.org/10.1038/35102591

A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. / Weggen, Sascha; Eriksen, Jason L.; Das, Pritam; Sagi, Sarah A.; Wang, Rong; Pietrzik, Claus U.; Findlay, Kirk A.; Smith, Tawnya E.; Murphy, Michael P.; Bulter, Thomas; Kang, David E.; Marquez-Sterling, Numa; Golde, Todd E.; Koo, Edward H.

In: Nature, Vol. 414, No. 6860, 08.11.2001, p. 212-216.

Research output: Contribution to journalArticle

Weggen, S, Eriksen, JL, Das, P, Sagi, SA, Wang, R, Pietrzik, CU, Findlay, KA, Smith, TE, Murphy, MP, Bulter, T, Kang, DE, Marquez-Sterling, N, Golde, TE & Koo, EH 2001, 'A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity', Nature, vol. 414, no. 6860, pp. 212-216. https://doi.org/10.1038/35102591
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-216. https://doi.org/10.1038/35102591
Weggen, Sascha ; Eriksen, Jason L. ; Das, Pritam ; Sagi, Sarah A. ; Wang, Rong ; Pietrzik, Claus U. ; Findlay, Kirk A. ; Smith, Tawnya E. ; Murphy, Michael P. ; Bulter, Thomas ; Kang, David E. ; Marquez-Sterling, Numa ; Golde, Todd E. ; Koo, Edward H. / A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. In: Nature. 2001 ; Vol. 414, No. 6860. pp. 212-216.
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