title: Histone acetyltransferase p300 mediates histone acetylation of PS1 and BACE1 in a cellular model of Alzheimer's disease.
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.
authors: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China; Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors: Xi
authors: X
authors: Lu
authors: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China; Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors: Yushuang
authors: Y
authors: Deng
authors: Department of Clinical Sciences, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: Daohai
authors: D
authors: Yu
authors: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China; Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors: Huiming
authors: H
authors: Cao
authors: Department of Bio-therapy & Hemato-oncology, Chingqing Cancer Institute, Chongqing, P.R. China.
authors: Li
authors: L
authors: Wang
authors: Department of Neurology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, P.R. China.
authors: Li
authors: L
authors: Liu
authors: Genetics and Molecular Biology, Northwestern University, Evanston, Illinois, United States of America.
authors: Caijia
authors: C
authors: Yu
authors: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors: Yuping
authors: Y
authors: Zhang
authors: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors: Xiuming
authors: X
authors: Guo
authors: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, P.R. China.
authors: Gang
authors: G
authors: Yu
mesh_terms: D000107:Acetylation; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014162:Transfection
chemical_list: D016564:Amyloid beta-Protein Precursor; D006657:Histones; D053764:Presenilin-1; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse