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Selective inhibition of PCAF suppresses microglial-mediated β-amyloid neurotoxicity

Authors
 Soo-Yeon Park ; Yoo-Hyun Lee ; Ah-Reum Seong ; Jeongmin Lee ; Woojin Jun ; Ho-Geun Yoon 
Citation
 International Journal of Molecular Medicine, Vol.32(2) : 469~475, 2013 
Journal Title
 International Journal of Molecular Medicine 
ISSN
 1107-3756 
Issue Date
2013
Abstract
Recent studies have emphasized the functional role of the P300/CBP-associated factor (PCAF) enzyme in resistance to β-amyloid (Aβ)-mediated neurotoxicity; however, the underlying mechanisms through which PCAF regulates inflammation and neurotoxicity have not yet been elucidated. In this study, we used computer-based molecular docking simulations to perform structure-based artificial screening for PCAF-specific inhibitors. Our results revealed that one of the compounds from the screened library, compound C-11, selectively inhibited PCAF, but not p300 or GCN5, with a half-maximal inhibitory concentration (IC50) of approximately 0.25 µM. Furthermore, C-11 had no effects on the activities of other epigenetic enzymes. Western blot analysis using an antibody against acetyl-nuclear factor-κB (NF-κB) demonstrated that PCAF mediated the Aβ-induced activation of NF-κB by acetylation at Lys-122. We also found that the knockdown of PCAF completely inhibited Aβ-induced cytokine production in BV-2 cells in a similar manner to C-11 treatment. Finally, PCAF inhibition suppressed both Aβ-induced cytokine production and Aβ-mediated neuronal cell death. Therefore, our results suggest that in neuronal cells, PCAF is a promising therapeutic target for alleviating the inflammatory progression of Alzheimer's disease.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/87190
DOI
10.3892/ijmm.2013.1407
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Biochemistry & Molecular Biology
Yonsei Authors
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Link
 http://www.spandidos-publications.com/ijmm/32/2/469
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