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

Park,Soo-Yeon; Lee,Yoo-Hyun; Seong,Ah-Reum; Lee,Jeongmin; Jun,Woojin; Yoon,Ho-Geun

doi:10.3892/ijmm.2013.1407

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
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Affiliations: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun‑gu, Seoul 120-752, Republic of Korea, Department of Food Science and Nutrition, University of Suwon, Suwon, Kyunggi‑do 445-743, Republic of Korea, Department of Medical Nutrition, Kyung Hee University, Yongin-si, Kyunggi-do 446-701, Republic of Korea, Department of Food and Nutrition, Chonnam National University, Buk-Gu, Gwangju 500-757, Republic of Korea
Published online on: June 5, 2013 https://doi.org/10.3892/ijmm.2013.1407
Pages: 469-475

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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.

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