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(American Journal of Pathology. 2004;165:2197-2206.)
© 2004 American Society for Investigative Pathology

Modulation of Nuclear Factor-{kappa}B Activity by Indomethacin Influences Aß Levels but Not Aß Precursor Protein Metabolism in a Model of Alzheimer’s Disease

Syaun Sung*, Hengxuan Yang*, Kunihiro Uryu{dagger}, Edward B. Lee{dagger}, Lei Zhao*, Diana Shineman{dagger}, John Q. Trojanowski{dagger}{ddagger}, Virginia M.-Y. Lee{dagger}{ddagger} and Domenico Praticò*

From the Department of Pharmacology,* Center for Experimental Therapeutics, the Center for Neurodegenerative Disease Research,{dagger} and the Institute on Aging,{ddagger} University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer’s disease (AD). We determined the impact of two nonsteroidal anti-inflammatory drugs on Aß levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced Aß1-40 and Aß1-42 levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-{kappa}B activity. By contrast, nimesulide had no effect on both Aß peptides and NF-{kappa}B. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of Aß peptides or the Aß precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti-amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-{kappa}B significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.




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