Journal
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
Volume 32, Issue 2, Pages 469-475Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijmm.2013.1407
Keywords
histone acetyltransferase; P300/CBP-associated factor; inflammation; nuclear factor-kappa B; neurotoxicity; beta-amyloid; cytokine
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Funding
- Korea Health Care Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea [A092039]
- Korea Health Promotion Institute [A092039] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Recent studies have emphasized the functional role of the P300/CBP-associated factor (PCAF) enzyme in resistance to beta-amyloid (A beta)-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 mu M. Furthermore, C-11 had no effects on the activities of other epigenetic enzymes. Western blot analysis using an antibody against acetyl-nuclear factor-kappa B (NF-kappa B) demonstrated that PCAF mediated the A beta-induced activation of NF-kappa B by acetylation at Lys-122. We also found that the knockdown of PCAF completely inhibited A beta-induced cytokine production in BV-2 cells in a similar manner to C-11 treatment. Finally, PCAF inhibition suppressed both A beta-induced cytokine production and A beta-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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