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 HMOX1expression. 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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in the death of nerve cells, deterioration of cognitive function [1], and eventual death from complications
Increased heme oxygenase-1 (HMOX1) mRNA expression and protein expression were observed in the hippocampus of 12-month-old amyloid precursor protein (APP) swe/PSEN1 transgenic mice (Borchelt; B6C3-Tg(APP695) 85Dbo/Tg(PSEN1)85Dbo) compared with wild-type mice, HMOX1 mRNA and protein levels remained unchanged in the frontal cortex and cerebellum of transgenic mice (Fig 1C and 1D)
Previous studies show that HMOX1 expression is up-regulated in cortical and hippocampal neurons and astrocytes in patients with AD or mild cognitive impairment (MCI), whereas its expression is faint or undetectable in age-matched normal tissue [14, 37]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that results in the death of nerve cells, deterioration of cognitive function [1], and eventual death from complications. It is the most common form of age-related dementia, with its incidence approaching 50% in people over 85 years of age [2]. Other potential diagnostic biochemical methods include detecting the level of amyloid beta (Aβ) or tau protein in the cerebrospinal fluid (CSF) [5,6,7] or serum [8, 9], or the level of glial fibrillary acidic protein [10]. The convenience and accuracy of these methods remain questionable
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