Inhibitors of Rho-kinase modulate amyloid-β (Aβ) secretion but lack selectivity for Aβ42

Abstract

Certain non-steroidal anti-inflammatory drugs (NSAIDs) preferentially inhibit production of the amyloidogenic Aβ42 peptide, presumably by direct modulation of γ-secretase activity. A recent report indicated that NSAIDs could reduce Aβ42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Aβ42-lowering NSAIDs. To investigate whether Aβ42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Aβ42-lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Aβ secretion in a dose-dependent manner but showed no selectivity for Aβ42. In addition, ROCK inhibitors did not increase Aβ38 secretion in cell-based assays or reduce Aβ production in γ-secretase in vitro assays, which are critical characteristics of Aβ42-lowering NSAIDs. The reduction in total Aβ levels by ROCK inhibitors was not accompanied by overall-changes in amyloid precursor protein processing. Targeting ROCK by expression of dominant-negative or constitutively active ROCK mutants failed to modulate Aβ secretion, indicating that ROCK inhibition may either be redundant or insufficient for Aβ reduction by ROCK inhibitors. Taken together, these results seem to exclude a mechanistic involvement of ROCK in the Aβ42-lowering activity of NSAIDs. © 2005 International Society for Neurochemistry.