Histone Acetylase P300Mediates Histone Acetylation Of PS1and BACE1in A Cellular Model Of Alzheimer’s Disease

Epigenetic modifications, particularly histone acetylation, have beenimplicated in Alzheimer’s disease (AD). While previous studies havesuggested that histone hypoacetylation may regulate the expression ofgenes associated with memory and learning in AD, little is known abouthistone regulation of AD-related genes such as Presenilin1(PS1) andbeta-site amyloid precursor protein cleaving enzyme1(BACE1). Byutilizing neuroblastoma N2a cells transfected with Swedish mutatedhuman amyloid precursor protein (APP)(N2a/APPswe) and wild-typeAPP (N2a/APPwt) as cellular models of AD, we examined the alterationsof histone acetylation at the promoter regions of PS1and BACE1in thesecells. Our results revealed that histone H3acetylation in PS1and BACE1promoters is markedly increased in N2a/APPswe cells when compared toN2a/APPwt cells and control cells (vector-transfected), respectively,causing the elevated expression of PS1and BACE1. In addition,expression of histone acetylase (HAT) adenoviral E1A-associated300-kDa protein (p300) is dramatically enhanced in N2a/APPswe cellscompared to N2a/APPwt and control cells. We have further demonstratedthe direct binding of p300protein to the PS1and BACE1promoters inN2a/APPswe cells. The expression levels of H3acetylation of the PS1andBACE1promoters and p300protein, however, were found to be not significantly different in N2a/APPwt cells when compared to controls inour studies. Furthermore, curcumin, a natural selective inhibitor of p300inHATs, significantly suppressed the expression of PS1and BACE1throughinhibition of H3acetylation in their promoter regions in N2a/APPswe cells.These findings indicated that histone acetylase p300plays a critical role incontrolling the expression of AD-related genes through regulating theacetylation of their promoter regions, suggesting that p300may representa novel potential therapeutic target for AD.