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 Abeta42 peptide, presumably by direct modulation of gamma-secretase activity. A recent report indicated that NSAIDs could reduce Abeta42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Abeta42-lowering NSAIDs. To investigate whether Abeta42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Abeta42-lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Abeta secretion in a dose-dependent manner but showed no selectivity for Abeta42. In addition, ROCK inhibitors did not increase Abeta38 secretion in cell-based assays or reduce Abeta production in gamma-secretase in vitro assays, which are critical characteristics of Abeta42-lowering NSAIDs. The reduction in total Abeta 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 Abeta secretion, indicating that ROCK inhibition may either be redundant or insufficient for Abeta reduction by ROCK inhibitors. Taken together, these results seem to exclude a mechanistic involvement of ROCK in the Abeta42-lowering activity of NSAIDs.