Histone acetyltransferase p300 mediates histone acetylation of PS1 and BACE1 in a cellular model of Alzheimer's disease.

Xi Lu,Li Liu,Li Wang,Huiming Cao,Yushuang Deng,Daohai Yu,Xiuming Guo,Yuping Zhang,Gang Yu,Caijia Yu,Jaya Padmanabhan

doi:10.1371/journal.pone.0103067

Abstract

Epigenetic modifications, particularly histone acetylation, have been implicated in Alzheimer's disease (AD). While previous studies have suggested that histone hypoacetylation may regulate the expression of genes associated with memory and learning in AD, little is known about histone regulation of AD-related genes such as Presenilin 1(PS1) and beta-site amyloid precursor protein cleaving enzyme 1(BACE1). By utilizing neuroblastoma N2a cells transfected with Swedish mutated human amyloid precursor protein (APP) (N2a/APPswe) and wild-type APP (N2a/APPwt) as cellular models of AD, we examined the alterations of histone acetylation at the promoter regions of PS1 and BACE1 in these cells. Our results revealed that histone H3 acetylation in PS1 and BACE1 promoters is markedly increased in N2a/APPswe cells when compared to N2a/APPwt cells and control cells (vector-transfected), respectively, causing the elevated expression of PS1 and BACE1. In addition, expression of histone acetyltransferase (HAT) adenoviral E1A-associated 300-kDa protein (p300) is dramatically enhanced in N2a/APPswe cells compared to N2a/APPwt and control cells. We have further demonstrated the direct binding of p300 protein to the PS1 and BACE1 promoters in N2a/APPswe cells. The expression levels of H3 acetylation of the PS1 and BACE1 promoters and p300 protein, however, were found to be not significantly different in N2a/APPwt cells when compared to controls in our studies. Furthermore, curcumin, a natural selective inhibitor of p300 in HATs, significantly suppressed the expression of PS1 and BACE1 through inhibition of H3 acetylation in their promoter regions in N2a/APPswe cells. These findings indicated that histone acetyltransferase p300 plays a critical role in controlling the expression of AD-related genes through regulating the acetylation of their promoter regions, suggesting that p300 may represent a novel potential therapeutic target for AD.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder [1]
We examined by ELISA the histone acetyltransferase (HAT) activity that is involved in the alteration of histone acetylation and found it to be significantly increased in the N2a/APPswe cells but not in the N2a/APPwt cells compared to the controls (Figure 3C)
In line with the increased expression levels, the histone H3 in the promoter regions of the PS1 and BACE1 was found to be hyperacetylated in N2a/APPswe cells, which resulted in enhanced transcriptional activities

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder [1]. Numerous studies have indicated that epigenetic modification is involved in the etiology of AD [2]. Several studies have reported histone hypoacetylation in genes related to memory and synapsis plasticity, indicating that decreased histone acetylation is associated with AD [3,4]. Marambaud et al found that PS1 mutations related to familial AD repress proteasomal degradation of HAT CREB-binding protein (CBP) and upregulate CREB-mediated gene transcription in murine neuronal cells [7]. These inconsistent results indicated that the levels of histone acetylation vary depending on brain regions, animal models, cell types and gene loci [10]. Little direct evidence has been presented to link AD-related genes to histone modification

Methods

Results

Conclusion