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Science 14 November 2003:
Vol. 302. no. 5648, pp. 1215 - 1217
DOI: 10.1126/science.1090154
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Reports

Nonsteroidal Anti-Inflammatory Drugs Can Lower Amyloidogenic Aß42 by Inhibiting Rho

Yan Zhou,* Yuan Su, Baolin Li, Feng Liu, John W. Ryder, Xin Wu, Patricia A. Gonzalez-DeWhitt, Valentina Gelfanova, John E. Hale, Patrick C. May, Steven M. Paul,* Binhui Ni

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-ß peptide Aß42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Aß42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Aß42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Aß42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Aß42 through inhibition of Rho activity.

Neuroscience Discovery Research and Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.

* To whom correspondence should be addressed. E-mail: paul_steven_m{at}lilly.com; zhou_yan_yz{at}lilly.com

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