A subset of NSAIDs lower amyloidogenic A beta 42 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 mec hanism has not been proved. Here we report that the NSAIDs ibuprofen, indom ethacin and sulindac sulphide preferentially decrease the highly amyloidoge nic 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 wa s not seen in all NSAIDs and seems not to be mediated by inhibition of cycl ooxygenase (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 acco mpanied by an increase in the A beta (1-38) isoform, indicating that NSAIDs subtly alter gamma -secretase activity without significantly perturbing ot her APP processing pathways or Notch cleavage. Our findings suggest that NS AIDs directly affect amyloid pathology in the brain by reducing A beta 42 p eptide levels independently of COX activity and that this A beta 42-lowerin g activity could be optimized to selectively target the pathogenic A beta 4 2 species.