Inhibitors of Rho-kinase modulate amyloid-beta (Abeta) secretion but lack selectivity for Abeta42.
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.
Leuchtenberger
Stefanie
S
Emmy Noether Research Group, Institute of Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University Mainz, Mainz, Germany.
Kummer
Markus P
MP
Kukar
Thomas
T
Czirr
Eva
E
Teusch
Nicole
N
Sagi
Sarah A
SA
Berdeaux
Rebecca
R
Pietrzik
Claus U
CU
Ladd
Thomas B
TB
Golde
Todd E
TE
Koo
Edward H
EH
Weggen
Sascha
S
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D010450:Endopeptidases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000506:poisoning; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D054460:rho-Associated Kinases
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C078639:amyloid beta-protein (1-38); C075222:amyloid beta-protein (1-42); D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human