Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer's Disease

• Published in: PloS one Vol. 11; no. 4; p. e0153156
• Main Authors: Sung, Hye Youn, Choi, Byung-Ok, Jeong, Jee Hyang, Kong, Kyoung Ae, Hwang, Jinha, Ahn, Jung-Hyuck
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-04-2016; Public Library of Science (PLoS)
• Subjects: Aberration; Aged; Aged, 80 and over; Aging; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Alzheimer's disease; Amyloid beta-protein; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Analysis; Animals; Biochemistry; Biology and life sciences; Biomarkers; Brain; Case-Control Studies; Cell Line; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - psychology; Control; CpG Islands; Dementia; Demethylation; Deoxyribonucleic acid; Diagnosis; Diagnostic software; Diagnostic systems; Disease Progression; DNA; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic; Epigenetics; Female; Gene expression; Gene regulation; Genetic Markers; Heat shock proteins; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Impairment; Jurkat Cells; Leukemia; Lymphocytes; Lymphocytes T; Male; Medicine; Medicine and Health Sciences; Mental Status Schedule; Mice; Mice, Transgenic; Middle Aged; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Neurodegenerative diseases; Neurofibrillary tangles; Neurology; NMR; Nuclear magnetic resonance; Oxidative stress; Oxygenase; Pathogenesis; Patients; Penicillin; Polymerase chain reaction; Promoter Regions, Genetic; Protein folding; Proteins; Regulatory mechanisms (biology); Research and Analysis Methods; Risk factors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Senile plaques; Transgenic mice; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0153156

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.