Nonsteroidal Anti-Inflammatpry Drugs Can Lower Amyloidogenic Aβ ₄₂ 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 Aβ ₄₂ 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 Aβ ₄₂ 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.