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

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 b-amyloid (A beta)-mediated neurotoxicity, particularly the p300/CBP-associated factor (PCAF) enzyme. We recently reported the potential utility of a PCAF inhibitor in the suppression of A beta-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-kappa B (NF-kappa B) at Lys-122 and suppressed the NF-kappa B-mediated inflammatory response induced by lipopolysaccharide (LPS) or Aa 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 A beta-treated rats. In conclusion, our results demonstrate that this selective PCAF inhibitor has the potential to reduce the neuroinflammatory response induced by A beta.