By Karla Gale

WESTPORT, CT (Reuters Health) – Nonsteroidal anti-inflammatory agents (NSAIDs) appear to mediate amyloid pathology in the brain through a mechanism independent of their cyclooxygenase (COX) activity, investigators report in the November 8th issue of Nature.

Some NSAIDs have previously been associated with reduced risk of Alzheimer's disease and a decline in the deposition of amyloid plaques in the brain (see Reuters Health reports, November 21 and March 22, 2000). In addition, A-beta-42 peptide is increased in presenilin mutations and in most beta-amyloid precursor protein mutations that cause early-onset familial Alzheimer's disease.

In findings that co-author Dr. Edward H. Koo, of the University of California San Diego in La Jolla, calls "surprising," certain NSAIDs proved capable of reducing A-beta-42 peptide levels.

The investigators incubated the non-selective COX inhibitors sulindac sulphide, ibuprofen, and indomethacin with Chinese hamster ovary cells. All three drugs inhibited secretion of A-beta-42 in a dose-dependent matter, but total A-beta peptide levels were unaffected. However, negative results were obtained with aspirin, meloxicam, and celecoxib.

Treatment of fibroblasts deficient in COX-1 and COX-2 enzymes with sulindac sulphide showed similarly reduced levels of A-beta-42, demonstrating that the reduction in A-beta-42 was not mediated by inhibiting COX activity. Cells treated with sulindac sulphide showed increased secretion of A-beta-38.

"What's surprising is no one has ever found compounds that specifically target A-beta-42," Dr. Koo told Reuters Health. "Also, the mechanism is unusual. It 'flips' the cleavage event [of the amyloid precursor protein], so that rather than just inhibiting A-beta-42, the effective NSAIDs seem to switch the cleavage from the 42-residue fragment to the 38-residue fragment."

He noted that it is "very likely" that compounds that optimize A-beta-42 reduction without inhibiting COX activity will be identified. The problem, he said, is that "we have yet to find anything that's effective at low doses."

"The excitement will be if it really does work and drug companies can find a compound without COX activity, which they could take to high doses without the side effects associated with COX," Dr. Koo concluded.

Drs. Bart De Strooper and Gerhard Kצnig, of the Flanders Interuniversitary Institute in Leuven, Belgium, and of Bayer AG in Wuppertal, Germany, respectively, suggest that such a class of compounds need not be identified before patients can benefit.

"Researchers already have a wealth of clinical experience with NSAIDs," they write. They recommendation that the effects of these drugs on Alzheimer's disease be tested in clinical trials.

Nature 2001;414:159-160,212-216.