title: Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain.
abstract: DNA methylation (5-methylcytosine [5mC]) is one of several epigenetic markers altered in Alzheimer's disease (AD) brain. More recently, attention has been given to DNA hydroxymethylation (5-hydroxymethylcytosine [5hmC]), the oxidized form of 5mC. Whereas 5mC is generally associated with the inhibition of gene expression, 5hmC has been associated with increased gene expression and is involved in cellular processes such as differentiation, development, and aging. Recent findings point toward a role for 5hmC in the development of diseases including AD, potentially opening new pathways for treating AD through correcting methylation and hydroxymethylation alterations. In the present study, levels of 5mC and 5hmC were investigated in the human middle frontal gyrus (MFG) and middle temporal gyrus (MTG) by immunohistochemistry. Immunoreactivity for 5mC and 5hmC were significantly increased in AD MFG (N = 13) and MTG (N = 29) compared with age-matched controls (MFG, N = 13 and MTG, N = 29). Global levels of 5mC and 5hmC positively correlated with each other and with markers of AD including amyloid beta, tau, and ubiquitin loads. Our results showed a global hypermethylation in the AD brain and revealed that levels of 5hmC were also significantly increased in AD MFG and MTG with no apparent influence of gender, age, postmortem delay, or tissue storage time. Using double-fluorescent immunolabeling, we found that in control and AD brains, levels of 5mC and 5hmC were low in astrocytes and microglia but were elevated in neurons. In addition, our colocalization study showed that within the same nuclei, 5mC and 5hmC mostly do not coexist. The present study clearly demonstrates the involvement of 5mC and 5hmC in AD emphasizing the need for future studies determining the exact time frame of these epigenetic changes during the progression of AD pathology.
authors.affiliation: Departments of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand; Gravida National Centre for Growth and Development, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, The University of Auckland, Auckland, New Zealand.
authors.forename: Natacha
authors.initials: N
authors.lastname: Coppieters
authors.affiliation: Centre for Brain Research, The University of Auckland, Auckland, New Zealand; Department of Anatomy with Radiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Birger V
authors.initials: BV
authors.lastname: Dieriks
authors.affiliation: Centre for Brain Research, The University of Auckland, Auckland, New Zealand; Department of Anatomy with Radiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Claire
authors.initials: C
authors.lastname: Lill
authors.affiliation: Centre for Brain Research, The University of Auckland, Auckland, New Zealand; Department of Anatomy with Radiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.affiliation: Centre for Brain Research, The University of Auckland, Auckland, New Zealand; Department of Anatomy with Radiology, The University of Auckland, Auckland, New Zealand.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Curtis
authors.affiliation: Departments of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand; Gravida National Centre for Growth and Development, The University of Auckland, Auckland, New Zealand; Centre for Brain Research, The University of Auckland, Auckland, New Zealand. Electronic address: m.dragunow@auckland.ac.nz.
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000502:physiology* / Q000031:analogs & derivatives; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001253:Astrocytes / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D008297:Male; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D020534:Parahippocampal Gyrus / Q000378:metabolism
chemical_list: D005819:Genetic Markers; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
keywords: 5-Hydroxymethylcytosine (5hmC); 5-Methylcytosine (5mC); Alzheimer's disease; DNA hydroxymethylation; DNA methylation; Epigenetics; Human brain