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

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-β peptide Aβ 42 . We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Aβ 42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Aβ 42 . Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Aβ 42 in a transgenic mouse model of Alzheimer9s disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Aβ 42 through inhibition of Rho activity.