A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

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 A beta 42 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(6). Furthermore, short-term administration of ibuprofen to mice that produce mutant beta -amyloid precursor protein (APP) lowered their brain levels of A beta 42. In cultured cells, the decrease in A beta 42 secretion was accompanied by an increase in the A beta (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 A beta 42 peptide levels independently of COX activity and that this A beta 42-lowering activity could be optimized to selectively target the pathogenic A beta 42 species.