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 Aβ42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Aβ42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Aβ42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Aβ42 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 Aβ42 through inhibition of Rho activity.

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