Hostname: page-component-89b8bd64d-rbxfs Total loading time: 0 Render date: 2026-05-08T22:38:05.471Z Has data issue: false hasContentIssue false
  • English
  • Français

Changes in methylation patterns of multiple genes from peripheral blood leucocytes of Alzheimer's disease patients

Published online by Cambridge University Press:  21 February 2013

Yaping Hou ,
Huayun Chen ,
Qiong He ,
Wei Jiang ,
Tao Luo ,
Jinhai Duan ,
Nan Mu ,
Yunshao He  and
Huaqiao Wang
Yaping Hou
Affiliation:
Department of Anatomy & Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
Huayun Chen
Affiliation:
Daan Gene Diagnostic Center, Sun Yat-sen University, Guangzhou, PR China
Qiong He
Affiliation:
Department of Anatomy & Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
Wei Jiang
Affiliation:
Department of Anatomy & Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
Tao Luo
Affiliation:
Department of Anatomy & Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
Jinhai Duan
Affiliation:
East Department of Neurology, Guangdong General Hospital, Guangzhou, PR China Guangdong Academy of Medical Sciences, Guangzhou, PR China Guangdong Institute of Geriatrics, Guangzhou, PR China
Nan Mu
Affiliation:
Guangzhou Brain Hospital, Guangzhou, PR China
Yunshao He
Affiliation:
Daan Gene Diagnostic Center, Sun Yat-sen University, Guangzhou, PR China
Huaqiao Wang*
Affiliation:
Department of Anatomy & Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, PR China
*
Huaqiao Wang, Department of Anatomy & Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong province, PR China. Tel: +8602087332218; Fax: +8602084112545; E-mail: whuaqiao@yahoo.com.cn
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Efforts aiming at identifying biomarkers and corresponding methods for early diagnosis of Alzheimer's disease (AD) might be the most appropriate strategy to initiate promising new treatments and/or prevention of AD

Objective

The aim of our study is to assess the association of DNA methylation pattern of various leucocyte genes with AD pathogenesis in order to find potential biomarkers and corresponding methods for molecular diagnosis of AD.

Methods

DNA methylation level of various genes in AD patients and normal population were compared by bisulphite sequencing PCR and methylation-specific PCR (MSP). Furthermore, real-time PCR was used to explore the effects of DNA methylation on the expression of target genes.

Results

Results showed significant hypermethylation of mammalian orthologue of Sir2 (SIRT1) gene in AD patients compared with normal population. Meanwhile, changes in methylation level of SIRT1 gene between different severities of AD were also found. Specific primers were designed from the SIRT1 CpG islands to differentiate AD and control group by MSP method. Besides, significant demethylation of β-amyloid precursor protein (APP) gene was observed in AD patients, whereas no difference was observed in other AD-related genes. Moreover, significant decrease in expression of SIRT1 gene and increase in expression of APP gene were also found in AD patients. In addition, the expression level of SIRT1/APP genes was associated with the severity, but not with the age or gender, of AD patients.

Conclusion:SIRT1 and APP might be the interesting candidate biomarkers and valuable for clinical diagnosis or treatment of AD.

Keywords

Alzheimer's diseasebisulphite sequencing PCRDNA methylationSIRT1

Information

Type
Original Articles
Information
Acta Neuropsychiatrica , Volume 25 , Issue 2 , April 2013 , pp. 66 - 76
Copyright
Copyright © Scandinavian College of Neuropsychopharmacology 2013

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

1Zetzsche, T, Rujescu, D, Hardy, J, Hampel, H. Advances and perspectives from genetic research: development of biological markers in Alzheimer's disease. Expert Rev Mol Diagn 2010;10:667–690.Google Scholar
2Marques, SC, Oliveira, CR, Outeiro, TF, Pereira, CM. Alzheimer's disease: the quest to understand complexity. J Alzheimers Dis 2010;21:373–383.Google Scholar
3Pasinetti, GM. Use of cDNA microarray in the search for molecular markers involved in the onset of Alzheimer's disease dementia. J Neurosci Res 2001;65:471–476.Google Scholar
4Elmoualij, B, Dupiereux, I, Seguin, Jet al. Alzheimer's diseases: towards biomarkers for an early diagnosis, In: de la Monte, S, ed. The clinical spectrum of Alzheimer's disease–the charge toward comprehensive diagnostic and therapeutic strategies. In Tech, 2011: 221–242.Google Scholar
5Boss, MA. Diagnostic approaches to Alzheimer's disease. Biochim Biophys Acta >2000;1502:188–200.Google Scholar
6Wiltfang, J, Lewczuk, P, Riederer, Pet al. Consensus paper of the WFSBP task force on biological markers of dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World J Biol Psychiatry 2005;6:69–84.Google Scholar
7Chouliaras, L, Rutten, BP, Kenis, Get al. Epigenetic regulation in the pathophysiology of Alzheimer's disease. Prog Neurobiol 2010;90:498–510.Google Scholar
8Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev 2002;16:6–21.CrossRefGoogle ScholarPubMed
9Pfister, JA, Ma, C, Morrison, BE, D’Mello, SR. Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS One 2008;3:e4090.Google Scholar
10Wojcik, M, Mac-Marcjanek, K, Wozniak, LA. Physiological and pathophysiological functions of SIRT1. Mini Rev Med Chem 2009;9:386–394.Google Scholar
11Liang, WS, Dunckley, T, Beach, TGet al. Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set. Physiol Genomics 2008;33:240–256.Google Scholar
12Liang, WS, Dunckley, T, Beach, TGet al. Neuronal gene expression in non-demented individuals with intermediate Alzheimer's disease neuropathology. Neurobiol Aging 2010;31:549–566.Google Scholar
13Mastroeni, D, Grover, A, Delvaux, E, Whiteside, C, Coleman, PD, Rogers, J. Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol Aging 2010;31:2025–2037.Google Scholar
14Weeraratna, AT, Kalehua, A, Deleon, Iet al. Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues. Exp Cell Res 2007;313:450–461.Google Scholar
15Barabash, A, Marcos, A, Ancín, Iet al. APOE, ACT and CHRNA7 genes in the conversion from amnestic mild cognitive impairment to Alzheimer's disease. Neurobiol Aging 2009;30:1254–1264.Google Scholar
16Bentahir, M, Nyabi, O, Verhamme, Jet al. Presenilin clinical mutations can affect gamma secretase activity by different mechanisms. J Neurochem 2006;96:732–742.Google Scholar
17Findeis, MA. The role of amyloid beta peptide 42 in Alzheimer's disease. Pharmacol Ther 2007;116:266–286.Google Scholar
18Migliore, L, Coppedè, F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res 2009;667:82–97.Google Scholar
19Morris, JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology 1993;43:2412–2414.CrossRefGoogle ScholarPubMed
20Livak, KJ, Schmittgen, TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 2001;25:402–408.Google Scholar
21Wang, SC, Oelze, B, Schumacher, A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS One 2008;3:e2698.Google Scholar
22Sperança, MA, Batista, LM, Lourenço Rda, Set al. Can the rDNA methylation pattern be used as a marker for Alzheimer's disease?. Alzheimers Dement 2008;4:438–442.Google Scholar
23Seshadri, S. Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer's disease?. J Alzheimers Dis 2006;9:393–398.Google Scholar
24Fuso, A, Nicolia, V, Cavallaro, RA, Scarpa, S. DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer's disease models. J Nutr Biochem 2011;22:242–251.Google Scholar
25Wang, J, Fivecoat, H, Ho, L, Pan, Y, Ling, E, Pasinetti, GM. The role of Sirt1: at the crossroad between promotion of longevity and protection against Alzheimer's disease neuropathology. Biochim Biophys Acta 2010;1804: 1690–1694.Google Scholar
26Wang, J, Ho, L, Qin, Wet al. Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J 2005;19:659–661.Google Scholar
27Julien, C, Tremblay, C, Emond, Vet al. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 2009;68:48–58.Google Scholar
28West, RL, Lee, JM, Maroun, LE. Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient. J Mol Neurosci 1995;6: 141–146.Google Scholar
29Tohgi, H, Utsugisawa, K, Nagane, Y, Yoshimura, M, Genda, Y, Ukitsu, M. Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res Mol Brain Res 1999;70:288–292.Google Scholar
30Jiang, S, Zhang, M, Ren, Det al. Enhanced production of amyloid precursor protein mRNA by peripheral mononuclear blood cell in Alzheimer's Disease. Am J Med Genet B Neuropsychiatr Genet 2003;118B:99–102.Google Scholar
31Gonen, N, Bram, EE, Assaraf, YG. PCFT/SLC46A1 promoter methylation and restoration of gene expression in human leukemia cells. Biochem Biophys Res Commun 2008;376:787–792.Google Scholar
32Ledoux, S, Nalbantoglu, J, Cashman, NR. Amyloid precursor protein gene expression in neural cell lines: influence of DNA cytosine methylation. Mol Brain Res 1994;24:140–144.Google Scholar
33Lahiri, DK, Maloney, B, Zawia, NH. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 2009;14:992–1003.Google Scholar
34Yi-Deng, J, Tao, S, Hui-Ping, Zet al. Folate and ApoE DNA methylation induced by homocysteine in human monocytes. DNA Cell Biol 2007;26:737–744.Google Scholar
35Tohgi, H, Utsugisawa, K, Nagane, Y, Yoshimura, M, Ukitsu, M, Genda, Y. The methylation status of cytosines in a tau gene promoter region alters with age to downregulate transcriptional activity in human cerebral cortex. Neurosci Lett 1999;275:89–92.Google Scholar
36Zawia, NH, Lahiri, DK, Cardozo-Pelaez, F. Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med 2009;46:1241–1249.CrossRefGoogle ScholarPubMed
37Fuso, A, Seminara, L, Cavallaro, RA, D’Anselmi, F, Scarpa, S. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 2005;28:195–204.Google Scholar
38Clark, SJ, Harrison, J, Paul, CL, Frommer, M. High sensitivity mapping of methylated cytosines. Nucleic Acids Res 1994;22:2990–2997.Google Scholar
39Debomoy, KL, Maloney, B. The “LEARn” (Latent Early–life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps. Exp Gerontol 2010;45:291–296.Google Scholar