title: Selective PCAF inhibitor ameliorates cognitive and behavioral deficits by suppressing NF-κB-mediated neuroinflammation induced by Aβ in a model of Alzheimer's disease.
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.
authors: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Soo-Yeon
authors: SY
authors: Park
authors: Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea.
authors: Mi-Jeong
authors: MJ
authors: Kim
authors: Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea.
authors: Young Jun
authors: YJ
authors: Kim
authors: Department of Food and Nutrition, The University of Suwon, Kyunggi-do, Republic of Korea.
authors: Yoo-Hyun
authors: YH
authors: Lee
authors: Jeollanamdo Institute of Natural Resources Research, Jeonnam, Republic of Korea.
authors: Donghyuk
authors: D
authors: Bae
authors: Jeollanamdo Institute of Natural Resources Research, Jeonnam, Republic of Korea.
authors: Sunoh
authors: S
authors: Kim
authors: College of Pharmacy, CHA University, Pocheon, Republic of Korea.
authors: Younghwa
authors: Y
authors: Na
authors: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Severance Medical Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Ho-Geun
authors: HG
authors: Yoon
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003071:Cognition / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors*; D000099224:p300-CBP-Associated Factor
chemical_list: D000109:Acetylcholine; D000110:Acetylcholinesterase; D016229:Amyloid beta-Peptides; D016207:Cytokines; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor