- Paper Report
- Open Access
NSAIDs reduce Alzheimer's independently of COX activity
- Cheryl Smythe1
© Biomed Central Ltd 2002
- Received: 4 January 2002
- Published: 15 January 2002
- Alzheimer's disease
- COX inhibitor
- sulindac sulphide
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of rheumatoid arthritis. NSAID users have previously been shown to have a reduced risk of developing Alzheimer's disease. The deposition of the 42-residue isomer of the amyloid-? peptide (A?42) is central to the pathogenesis of Alzheimer's disease. A?42 is generated by cleavage of the amyloid precursor protein (APP) by a ?-secretase that cleaves APP at different positions thereby generating peptides of different lengths. This study investigates the mechanism through which NSAIDs exert their protective effect against the development of Alzheimer's disease.
CHO cells, which do not normally express APP, were transfected with APP and a presenilin mutant that leads to elevated levels of A? peptide production. Treatment of these cells with the nonselective cyclooxygenase (COX) inhibitors sulindac sulphide, ibuprofen or indomethacin, led to a 50-70% decrease in A?42 levels. However, not all NSAIDs were capable of reducing A?42 levels: the nonselective COX inhibitor naproxen, the COX-2 specific inhibitor celecoxib and the COX-1 specific and COX-2 preferential inhibitors aspirin and meloxicam respectively all had no effect on A?42 levels, indicating that the A?42-lowering effect is independent of COX activity. Indeed, fibroblasts deficient in both COX-1 and COX-2 exhibited reduced levels of A?42 in response to sulindac sulphide. Ibuprofen, but not naproxen, also reduced brain A?42 levels by 39% in a mouse model of Alzheimer's disease. Mass spectrometric analysis showed that the reduction in A?42 levels following sulindac sulphide treatment was associated with a dose-dependent increase in the level of another APP-derived peptide A?(1-38). Therefore, NSAIDs are thought to subtly alter the activity of the APP-cleaving ?-secretase.
ELISA, western blotting, immunoprecipitation with mass spectrometry (IPMS)
in 't Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MMB Stricker BHC: Nonsteroidal anti-inflammatory drugs and the risk of Alzheimer's disease. N Eng J Med 2001, 345: 1515-21.