4.6 Article

Involvement of small GTPase RhoA in the regulation of superoxide production in BV2 cells in response to fibrillar Aβ peptides

Journal

CELLULAR SIGNALLING
Volume 25, Issue 9, Pages 1861-1869

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.05.023

Keywords

Amyloid-beta; BV2; Microglia; RhoA GTPase; Superoxide

Categories

Funding

  1. Korea Healthcare Technology R&D Project, Ministry of Health & Welfare, Republic of Korea [A084589]
  2. Hallym University [HRF-S-4-1]

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Fibrillar amyloid-beta (fA beta) peptide causes neuronal cell death, which is known as Alzheimer's disease. One of the mechanisms for neuronal cell death is the activation of microglia which releases toxic compounds like reactive oxygen species (ROS) in response to fA beta. We observed that fA beta rather than soluble form blocked BV2 cell proliferation of microglial cell line BV2, while N-acetyl-L-cysteine (NAC), a scavenger of superoxide, prevented the cells from death, suggesting that cell death is induced by ROS. Indeed, both fA beta(1-42) and fA beta(25-35) induced superoxide production in BV2 cells. fA beta(25-35) produced superoxide, although fA beta(25-35) is not phagocytosed into BV2 cells. Thus, superoxide production by fA beta does not seem to be dependent on phagocytosis of fA beta. Herein we studied how fA beta produces superoxide in BV2. Transfection of dominant negative (DN) RhoA (N19) cDNA plasmid, small hairpin (sh)-RhoA forming plasmid, and Y27632, an inhibitor of Rho-kinase, abrogated the superoxide formation in BV2 cells stimulated by fA beta. Furthermore, fA beta elevated GTP-RhoA level as well as Rac1 and Cdc42. Tat-C3 toxin, sh-RhoA, and Y27632 inhibited the phosphorylation of p47(PHOX). Moreover, peritoneal macrophages from p47(PHOX)(-/-) knockout mouse could not produce superoxide in response to fA beta. These results suggest that RhoA closely engages in the regulation of superoxide production induced by fA beta through phosphorylation of p47(PHOX) in microglial BV2 cells. (c) 2013 Elsevier Inc. All rights reserved.

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