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 and Edward H. Koo ()
Additional contact information
Sascha Weggen: University of California San Diego
Jason L. Eriksen: Mayo Clinic Jacksonville
Pritam Das: Mayo Clinic Jacksonville
Sarah A. Sagi: University of California San Diego
Rong Wang: Mount Sinai School of Medicine
Claus U. Pietrzik: University of California San Diego
Kirk A. Findlay: Mayo Clinic Jacksonville
Tawnya E. Smith: Mayo Clinic Jacksonville
Michael P. Murphy: Mayo Clinic Jacksonville
Thomas Bulter: California Institute of Technology
David E. Kang: University of California San Diego
Numa Marquez-Sterling: Northwestern University Medical School
Todd E. Golde: Mayo Clinic Jacksonville
Edward H. Koo: University of California San Diego

Nature, 2001, vol. 414, issue 6860, 212-216

Abstract: Abstract 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.

Date: 2001
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DOI: 10.1038/35102591

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