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.

journal_name

Int J Mol Med

authors

Park SY,Kim MJ,Kim YJ,Lee YH,Bae D,Kim S,Na Y,Yoon HG

doi

10.3892/ijmm.2015.2099

subject

Has Abstract

pub_date

2015-04-01 00:00:00

pages

1109-18

issue

4

eissn

1107-3756

issn

1791-244X

journal_volume

35

pub_type

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