EMBARGOED BY NATURE FOR 5 p.m. EST WEDNESDAY, NOV. 7, 2001

Selected NSAIDs Decrease Alzheimer’s Plaque-Forming Protein
Without Adverse Effects of Anti-Inflammatory Drugs

Researchers at the University of California, San Diego (UCSD) School of Medicine and the Mayo Clinic, Jacksonville, FL have shown in cell cultures and mice that certain nonsteroidal anti-inflammatory drugs (NSAIDs) use a novel mechanism to decrease the harmful amyloid-beta 42 protein (AB42) that forms brain plaques, a hallmark condition in Alzheimer’s disease patients.

Although some individuals who chronically take NSAIDs have shown reduced risk of developing Alzheimer’s disease, the mechanism of action of these drugs is unclear. NSAIDs are known to inhibit master enzymes called cyclooxygenases (COX), which control inflammatory responses. It therefore has been assumed by many researchers that NSAIDs are effective in Alzheimer’s disease by reducing toxic, inflammatory process in the brain.

However, the new findings, published in the Nov. 8, 2001 issue of the journal Nature, suggest that NSAID therapy has a direct impact on the cause of the disease, which is believed to be the abnormal deposition of AB42 in the brain.

Because the anti-inflammatory properties of NSAIDs can cause severe gastrointestinal and kidney problems, the new findings also offer hope for the development of highly effective plaque-reducing drugs without the toxic side effects associated with anti-inflammatory medications.

The research was led by first author Sascha Weggen, Ph.D., UCSD Department of Neurosciences, and senior authors Edward Koo, M.D., UCSD Department of Neurosciences and Todd E. Golde, M.D., Ph.D., Mayo Clinic, Jacksonville.

The new study is the first to demonstrate a specific pharmacological inhibition of AB42 production. Specifically, the NSAIDs ibuprofen, indomethacin and sulindac sulphide decreased AB42 by as much as 80 percent. Koo warned, however, that these results don’t mean that physicians should begin to prescribe these three drugs for Alzheimer’s patients.

“The dose required to inhibit production of AB42 is far too high. This is a secondary effect of the NSAIDs. For example, a patient would need to take the equivalent of more than 16 tablets of Advil a day,” he said. “Instead, our findings suggest a new mechanism through which NSAIDs might confer protection from Alzheimer’s disease – a mechanism independent of direct anti-inflammatory properties of NSAIDs. ”

Since not all NSAIDs are the same, the research team conducted their studies by treating rodent and human cells in laboratory culture dishes with various NSAIDs, then analyzing AB42 levels. While the NSAIDs ibuprofen, indomethacin and sulindac sulphide lowered AB42, other NSAIDs, including aspirin, Naproxen and celecoxib, had no effect on AB42. Similar results were found in studies with mice.

Koo noted that since many researchers and clinicians have proposed that NSAIDs are effective in Alzheimer’s disease by inhibiting COX enzymes and therefore inflammation, the UCSD/Mayo team tested this theory. They took cells genetically engineered to lack the COX enzymes and treated them with sulindac. The result – the lowering of AB42 levels – indicated that decrease of AB42 levels is completely independent of COX activity.

“These results provide compelling evidence that the reduction in AB42 is not mediated by inhibition of COX activity, the principle mode of action of NSAIDs,” the authors state in their Nature paper.

Additional authors of the Nature paper are Jason L. Eriksen, Ph.D., Pritam Das, Ph.D., Kirk A. Findlay, Ph.D., Tawnya E. Smith, B.A., and Michael P. Murphy, Ph.D., Mayo Clinic, Jacksonville; Sarah A. Sagl, Ph.D., Claus U. Pletrzik, Ph.D., and David E. Kang, Ph.D., UCSD Department of Neurosciences; Rong Wang, Ph.D., Mt. Sinai School of Medicine, New York; Thomas Bulter, Ph.D., California Institute of Technology, Pasadena; and Numa Marquez-Sterling, M.D., Northwestern University Medical School, Chicago.

The work was supported by National Institutes of Health grants, a BeesonAward, an Ellison Medical Foundation New Scholars award, a Robert and Clarice Smith Fellowship, a John Duglas French Alzheimer’s Foundation Fellowship, and an Emmy Noether-fellowship from the Deutsche Forschungsgemeinschaft.

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Media Contacts:

 
Sue Pondrom
UCSD School of Medicine
La Jolla, CA
619-543-6163
spondrom@ucsd.edu

 

Erik Kaldor
May Clinic
Jacksonville, FL
904-953-2299
kaldor.erik@mayo.edu

UCSD Health Sciences Communications HealthBeat:  http://health.ucsd.edu/news/