title: Selective inhibition of PCAF suppresses microglial-mediated β-amyloid neurotoxicity.
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.
authors.affiliation: 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.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.forename: Yoo-Hyun
authors.initials: YH
authors.lastname: Lee
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Seong
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Lee
authors.forename: Woojin
authors.initials: W
authors.lastname: Jun
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003198:Computer Simulation; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D054852:Small Molecule Libraries; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000099224:p300-CBP-Associated Factor
chemical_list: D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D054852:Small Molecule Libraries; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor