title: Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer's Disease.
abstract: To identify epigenetically regulated genes involved in the pathogenesis of Alzheimer's disease (AD) we analyzed global mRNA expression and methylation profiles in amyloid precursor protein (APP)-Swedish mutant-expressing AD model cells, H4-sw and selected heme oxygenase-1 (HMOX1), which is associated with pathological features of AD such as neurofibrillary tangles and senile plaques. We examined the epigenetic regulatory mechanism of HMOX1 and its application as a diagnostic and prognostic biomarker for AD. Our results show that HMOX1 mRNA and protein expression was approximately 12.2-fold and 7.9-fold increased in H4-sw cells, respectively. Increased HMOX1 expression was also detected in the brain, particularly the hippocampus, of AD model transgenic mice. However, the methylation of specific CpG sites within its promoter, particularly at CpG located -374 was significantly decreased in H4-sw cells. Treatment of neuroglioma cells with the demethylating agent 5-aza-2'-deoxycytidine resulted in reduced methylation of HMOX1 promoter accompanied by enhanced HMOX1 expression strongly supporting DNA methylation-dependent transcriptional regulation of HMOX1. Toxic Aβ-induced aberrant hypomethylation of HMOX1 at -374 promoter CpG site was correlated with increased HMOX1 expression. In addition to neuroglioma cells, we also found Aβ-induced epigenetic regulation of HMOX1 in human T lymphocyte Jurkat cells. We evaluated DNA methylation status of HMOX1 at -374 promoter CpG site in blood samples from AD patients, patients with mild cognitive impairment (MCI), and control individuals using quantitative methylation-specific polymerase chain reaction. We observed lower methylation of HMOX1 at the -374 promoter CpG site in AD patients compared to MCI and control individuals, and a correlation between Mini-Mental State Examination score and demethylation level. Receiver operating characteristics analysis revealed good discrimination of AD patients from MCI patients and control individuals. Our findings suggest that the methylation status of HMOX1 at a specific promoter CpG site is related to AD progression.
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Hye Youn
authors.initials: HY
authors.lastname: Sung
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Byung-Ok
authors.initials: BO
authors.lastname: Choi
authors.affiliation: Department of Neurology, Ewha Womans University Mokdong Hospital, Seoul, Republic of Korea.
authors.forename: Jee Hyang
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Clinical Trial Center, Ewha Womans University Medical Center, Seoul, Republic of Korea.
authors.forename: Kyoung Ae
authors.initials: KA
authors.lastname: Kong
authors.affiliation: Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea.
authors.forename: Jinha
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.|Department of Biochemistry, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jung-Hyuck
authors.initials: JH
authors.lastname: Ahn
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism / Q000523:psychology; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D005819:Genetic Markers; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D008609:Mental Status Schedule; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D005819:Genetic Markers; D050505:Mutant Proteins; D012333:RNA, Messenger; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1