Bibliographic
The recognition that a robust inflammatory response is a component of the Alzheimer’s disease process led to the discovery that long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) dramatically reduced the risk for Alzheimer’s disease, and delayed disease onset. The mechanisms by which NSAIDs act to reduce AD risk are controversial. Some investigators have proposed NSAIDs reduce AD risk by dampening down inflammation in the brain via inhibition of cyclooxygenases (COX) 1 and 2;others have proposed that some NSAIDs reduce the risk for AD by selectively lowering the production of Abeta42.The overarching goal of this study was to examine whether treatment of cells and transgenic mice with non-steroidal anti-inflammatory drugs (NSAIDs) alters APP processing and generation of Abeta, particularly the Abeta 42 species. The study reports that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta 42 peptide produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seemed not to be mediated by inhibition of COX activity. These data suggest that alternative targets of NSAID action have to be considered.The short-term administration of ibuprofen to transgenic mice that produce mutant APP lowered their brain levels of Abeta 42. In cultured cells, the decrease in Abeta 42 secretion was accompanied by an increase in the Abeta(1±38) isoform, indicating that NSAIDs target gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage.These findings suggest that NSAIDs directly affect beta -amyloid pathology in the brain by reducing Abeta 42 peptide levels by altering gamma secretase activity on APP, and that this Abeta 42-lowering activity could be optimized to selectively target the pathogenic Abeta 42 species.