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Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease

Authors
 Soo-Yeon Park  ;  Mi-Jeong Kim  ;  Young Jun Kim  ;  Yoo-Hyun Lee  ;  Donghyuk Bae  ;  Sunoh Kim  ;  Younghwa Na  ;  Ho-Geun Yoon 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Vol.35(4) : 1109-1118, 2015 
Journal Title
 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 
ISSN
 1107-3756 
Issue Date
2015
MeSH
Acetylation/drug effects ; Acetylcholine/metabolism ; Acetylcholinesterase/metabolism ; Alzheimer Disease/metabolism* ; Alzheimer Disease/psychology ; Amyloid beta-Peptides/metabolism* ; Animals ; Behavior, Animal/drug effects* ; Cell Death/drug effects ; Cell Line ; Cognition/drug effects* ; Cytokines/biosynthesis ; Disease Models, Animal ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology* ; Mice ; Microglia/drug effects ; Microglia/metabolism ; NF-kappa B/metabolism* ; Neurons/drug effects ; Neurons/metabolism ; Rats ; p300-CBP Transcription Factors/antagonists & inhibitors*
Keywords
Alzheimer's disease ; P300/CBP-associated factor ; inflammation ; nuclear factor-κB ; neurotoxicity ; β-amyloid ; cognitive deficit
Abstract
Several recent studies have reported an association between neurodegeneration and histone modifications, such as acetylation, deacetylation and methylation. In addition, questions have been raised regarding a potential functional role for the histone acetylation enzymes in β-amyloid (Aβ)-mediated neurotoxicity, particularly the p300/CBP-associated factor (PCAF) enzyme. We recently reported the potential utility of a PCAF inhibitor in the suppression of Aβ-induced neuronal cell death, although the in vivo effectiveness of the PCAF inhibitor remained unclear. In this study, we modified the PCAF inhibitor by chemical derivatization and selected compound C-30-27 as the most potent PCAF inhibitor. We demonstrated that C-30-27 selectively inhibited acetylation-dependent nuclear factor-κB (NF-κB) at Lys-122 and suppressed the NF-κB-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aβ in both BV2 and Neuro-2A (N2A) cells. Finally, we demonstrated that C-30-27 improved cognitive deficits, as well as the capacity for locomotion and the damaged cholinergic system in the Aβ-treated rats. In conclusion, our results demonstrate that this selective PCAF inhibitor has the potential to reduce the neuroinflammatory response induced by Aβ.
Full Text
http://www.spandidos-publications.com/ijmm/35/4/1109
DOI
10.3892/ijmm.2015.2099
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Soo Yeon(박수연) ORCID logo https://orcid.org/0000-0003-3743-9554
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139489
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