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

6533b7dafe1ef96bd126e2bb

RESEARCH PRODUCT

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

Rebecca Berdeaux Todd E. Golde Stefanie Leuchtenberger Sascha Weggen Thomas B. Ladd Nicole Teusch Thomas Kukar Claus U. Pietrzik Eva Czirr Edward H. Koo Markus P. Kummer Sarah A. Sagi

subject

Cell Survival Mutant Peptide CHO Cells Protein Serine-Threonine Kinases Pharmacology Biochemistry Amyloid beta-Protein Precursor Cellular and Molecular Neuroscience Cricetulus Cricetinae Endopeptidases mental disorders Amyloid precursor protein Animals Aspartic Acid Endopeptidases Secretion Small GTPase Enzyme Inhibitors Rho-associated protein kinase chemistry.chemical_classification rho-Associated Kinases Amyloid beta-Peptides biology Anti-Inflammatory Agents Non-Steroidal Intracellular Signaling Peptides and Proteins In vitro toxicology Protein-Tyrosine Kinases Peptide Fragments nervous system diseases Biochemistry chemistry biology.protein Amyloid Precursor Protein Secretases Selectivity Protein Processing Post-Translational

description

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.

year	journal	country	edition	language
2005-11-23	Journal of Neurochemistry

https://doi.org/10.1111/j.1471-4159.2005.03553.x