Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.

doi:10.1016/J.NEUROBIOLAGING.2013.02.021

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Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.

Journal Article•DOI•

Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.

Leonidas Chouliaras¹, Diego Mastroeni¹, Diego Mastroeni², Elaine Delvaux², Andrew Grover², Gunter Kenis¹, Patrick R. Hof³, Harry W.M. Steinbusch¹, Paul D. Coleman², Bart P. F. Rutten¹, Daniel L.A. van den Hove¹, Daniel L.A. van den Hove⁴ - Show less +8 more•Institutions (4)

Maastricht University Medical Centre¹, Banner Health², Icahn School of Medicine at Mount Sinai³, University of Würzburg⁴

01 Sep 2013-Neurobiology of Aging (Elsevier)-Vol. 34, Iss: 9, pp 2091-2099

TL;DR: Human postmortem results strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.

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About: This article is published in Neurobiology of Aging.The article was published on 2013-09-01 and is currently open access. It has received 351 citations till now. The article focuses on the topics: DNA Hydroxymethylation & DNA methylation.

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Journal Article•DOI•

Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.

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Philip L. De Jager¹, Gyan Srivastava¹, Katie Lunnon², Jeremy D. Burgess³, Leonard C. Schalkwyk², Lei Yu⁴, Matthew L. Eaton⁵, Brendan T. Keenan¹, Jason Ernst⁵, Cristin McCabe⁶, Anna Tang¹, Towfique Raj¹, Joseph M. Replogle¹, Wendy Brodeur⁶, Stacey Gabriel⁶, High Seng Chai³, Curtis S. Younkin³, Steven G. Younkin³, Fanggeng Zou³, Moshe Szyf⁷, Charles B. Epstein⁶, Julie A. Schneider⁴, Bradley E. Bernstein⁸, Alexander Meissner⁵, Nilufer Ertekin-Taner³, Lori B. Chibnik¹, Manolis Kellis⁵, Jonathan Mill², David A. Bennett⁴ - Show less +25 more•Institutions (8)

Brigham and Women's Hospital¹, King's College London², Mayo Clinic³, Rush University Medical Center⁴, Massachusetts Institute of Technology⁵, Broad Institute⁶, McGill University⁷, Harvard University⁸

01 Sep 2014-Nature Neuroscience

TL;DR: The analyses suggest that DNA methylation changes may have a role in the onset of AD given that they were observed in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

...read moreread less

Abstract: We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

...read moreread less

720 citations

Journal Article•DOI•

History and progress of hypotheses and clinical trials for Alzheimer’s disease

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Pei-Pei Liu¹, Yi Xie¹, Xiao-Yan Meng¹, Jian-Sheng Kang¹•Institutions (1)

Zhengzhou University¹

23 Aug 2019-Signal Transduction and Targeted Therapy

TL;DR: It is proposed that fluoxetine, a selective serotonin reuptake inhibitor, has the potential to treat AD and the combination of hypometabolism and autophagy deficiency is likely to be a causative factor for AD.

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Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss along with neuropsychiatric symptoms and a decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, and neurofibrillary tangles in the brains of patients. There are various descriptive hypotheses regarding the causes of AD, including the cholinergic hypothesis, amyloid hypothesis, tau propagation hypothesis, mitochondrial cascade hypothesis, calcium homeostasis hypothesis, neurovascular hypothesis, inflammatory hypothesis, metal ion hypothesis, and lymphatic system hypothesis. However, the ultimate etiology of AD remains obscure. In this review, we discuss the main hypotheses of AD and related clinical trials. Wealthy puzzles and lessons have made it possible to develop explanatory theories and identify potential strategies for therapeutic interventions for AD. The combination of hypometabolism and autophagy deficiency is likely to be a causative factor for AD. We further propose that fluoxetine, a selective serotonin reuptake inhibitor, has the potential to treat AD.

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350 citations

Cites background from "Consistent decrease in global DNA m..."

...SAM is generated and maintained by coupling one-carbon metabolism and mitochondrial energy metabolism.169,170 α-KG, which is generated by the tricarboxylic acid cycle (TCA) cycle in mitochondria and the cytosol, is a cofactor of ten–eleven translocation methylcytosine dioxygenase DNA methylases, histone demethylases (HDMs) and the lysine demethylases KDMs/JMJDs.171,172 However, the activities of KDMs/JMJDs and TETs can be inhibited by fumarate, succinate, and 2-hydroxyglutarate.173 Mutations that affect the succinate dehydrogenase complex and fumarate hydratase can induce the accumulation of succinate and fumarate, respectively.174 Oxidized flavin adenine dinucleotide (FAD) is an essential cofactor of the HDM LSD1, a member of the KDM family.175 In addition, acetyl-CoA, the source of acetyl groups that are consumed by histone acetyltransferases, is generated by ATP citrate lyase and pyruvate dehydrogenase in the cytosol and mitochondria, respectively.176 In addition, oxidized nicotinamide adenine dinucleotide (NAD+) is a cofactor for sirtuins (SIRTs), a family of deacetylases that includes nuclear-localized SIRT1, SIRT6, and SIRT7, cytosolic SIRT2, and three mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) (Fig....
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...α-KG is a necessary cofactor for TET DNA methylases, histone demethylases (HDMs), and lysine demethylases KDMs/JMJDs.(167,168) Mitochondria also regulate the levels and redox state of FAD, a cofactor of the histone demethylase LSD1....
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...The metabolites of mitochondrial TCA, such as pyruvate, fumarate, malate, OAA, and α-KG, not only directly regulate energy production but also play an important role in the epigenetic regulation of neurons and longevity.164,173,187–189 For example, SAM provides methyl groups for histone and DNA methyltransferases (HMTs and DNMTs).165,166 α-KG is a necessary cofactor for TET DNA methylases, histone demethylases (HDMs), and lysine demethylases KDMs/JMJDs.167,168 Mitochondria also regulate the levels and redox state of FAD, a cofactor of the histone demethylase LSD1....
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Journal Article•DOI•

Homocysteine, B Vitamins, and Cognitive Impairment

[...]

A. David Smith¹, Helga Refsum², Helga Refsum¹•Institutions (2)

University of Oxford¹, University of Oslo²

18 Jul 2016-Annual Review of Nutrition

TL;DR: Trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process.

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Abstract: Moderately elevated plasma total homocysteine (tHcy) is a strong modifiable risk factor for vascular dementia and Alzheimer's disease. Prospectively, elevated tHcy is associated with cognitive decline, white matter damage, brain atrophy, neurofibrillary tangles, and dementia. Most homocysteine-lowering trials with folate and vitamins B6 and/or B12 tested as protective agents against cognitive decline were poorly designed by including subjects unlikely to benefit during the trial period. In contrast, trials in high-risk subjects, which have taken into account the baseline B vitamin status, show a slowing of cognitive decline and of atrophy in critical brain regions, results that are consistent with modification of the Alzheimer's disease process. Homocysteine may interact with both risk factors and protective factors, thereby identifying people at risk but also providing potential strategies for early intervention. Public health steps to slow cognitive decline should be promoted in individuals who are at r...

...read moreread less

320 citations

Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

[...]

Gyan Srivastava, Katie Lunnon, Jeremy D. Burgess, Lei Yu, Jason Ernst, Cristin McCabe, Anna Tang, Towfique Raj, Joseph M. Replogle, Wendy Brodeur, Stacey Gabriel, Curtis S. Younkin, Fanggeng Zou, Moshe Szyf, Alexander Meissner, Nilufer Ertekin-Taner, Manolis Kellis, Jonathan Mill, Philip L. De Jager, Leonard C. Schalkwyk, Matthew L. Eaton, Matthew L. Eaton, Brendan T. Keenan, High Seng Chai, Steven G. Younkin, Charles B. Epstein, Julie A. Schneider, Bradley E. Bernstein, Lori B. Chibnik, David A. Bennett - Show less +26 more

01 Aug 2014

TL;DR: The analyses suggest that DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

...read moreread less

Abstract: Here, we leverage a unique collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We find that the level of methylation at 71 of the 415,848 interrogated CpGs is significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validate 11 of the differentially methylated regions in an independent set of 117 subjects. Further, we functionally validate these CpG associations and identify the nearby genes whose RNA expression is altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD since (1) they are seen in presymptomatic subjects and (2) six of the validated genes connect to a known AD susceptibility gene network.

...read moreread less

320 citations

Journal Article•DOI•

The epigenetics of aging and neurodegeneration.

[...]

Roy Lardenoije¹, Artemis Iatrou¹, Gunter Kenis¹, Konstantinos Kompotis², Harry W.M. Steinbusch¹, Diego Mastroeni¹, Paul D. Coleman, Cynthia A. Lemere³, Patrick R. Hof⁴, Daniel L.A. van den Hove⁵, Bart P. F. Rutten¹ - Show less +7 more•Institutions (5)

Maastricht University¹, University of Lausanne², Brigham and Women's Hospital³, Icahn School of Medicine at Mount Sinai⁴, University of Würzburg⁵

01 Aug 2015-Progress in Neurobiology

TL;DR: Current knowledge about the major epigenetic mechanisms, including DNA methylation and DNA demethylation, chromatin remodeling and non-coding RNAs, as well as the involvement of these mechanisms in normal aging and in the pathophysiology of the most common neurodegenerative diseases are reviewed.

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314 citations

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References

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Journal Article•DOI•

Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals

[...]

Rudolf Jaenisch¹, Adrian Bird²•Institutions (2)

Massachusetts Institute of Technology¹, University of Edinburgh²

01 Mar 2003-Nature Genetics

TL;DR: Advances in the understanding of the mechanism and role of DNA methylation in biological processes are reviewed, showing that epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression.

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Abstract: Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.

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5,760 citations

"Consistent decrease in global DNA m..." refers background in this paper

...DNA methylation, 1 of the fundamental epigenetic mechanisms, regulates gene transcription and can result in long-term changes in cellular function (Jaenisch and Bird, 2003)....
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Journal Article•DOI•

Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1

[...]

Mamta Tahiliani¹, Kian Peng Koh¹, Yinghua Shen², William A. Pastor¹, Hozefa S. Bandukwala¹, Yevgeny Brudno², Suneet Agarwal¹, Lakshminarayan M. Iyer³, David R. Liu², L. Aravind³, Anjana Rao¹ - Show less +7 more•Institutions (3)

Harvard University¹, Howard Hughes Medical Institute², National Institutes of Health³

15 May 2009-Science

TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.

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Abstract: DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.

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5,155 citations

"Consistent decrease in global DNA m..." refers background in this paper

...DNA hydroxymethylation is a newly described epigenetic modification derived from the oxidation of methylated cytosines by ten-eleven translocation (TET) enzymes (Kriaucionis and Heintz, 2009; Tahiliani et al., 2009)....
[...]

Journal Article•DOI•

Alzheimer's Disease Is a Synaptic Failure

[...]

Dennis J. Selkoe¹•Institutions (1)

Brigham and Women's Hospital¹

25 Oct 2002-Science

TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.

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Abstract: In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.

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3,941 citations

"Consistent decrease in global DNA m..." refers background in this paper

...Furthermore, examination of correlations with markers associated with the disease, such as cognitive decline, synaptic deficits, and neuronal loss, is of high importance (Coleman and Yao, 2003; Rutten et al., 2005; Selkoe, 2002)....
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Journal Article•DOI•

The Nuclear DNA Base 5-Hydroxymethylcytosine Is Present in Purkinje Neurons and the Brain

[...]

Skirmantas Kriaucionis¹, Nathaniel Heintz¹•Institutions (1)

Howard Hughes Medical Institute¹

15 May 2009-Science

TL;DR: It is shown that, as well as 5mC in mammalian genomes, there are also significant amounts of 5-hydroxymethylcytosine (5hmC) in DNA of Purkinje neurons, which have large nuclei with apparently very little heterochromatin.

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Abstract: Despite the importance of epigenetic regulation in neurological disorders, little is known about neuronal chromatin. Cerebellar Purkinje neurons have large and euchromatic nuclei, whereas granule cell nuclei are small and have a more typical heterochromatin distribution. While comparing the abundance of 5-methylcytosine in Purkinje and granule cell nuclei, we detected the presence of an unusual DNA nucleotide. Using thin-layer chromatography, high-pressure liquid chromatography, and mass spectrometry, we identified the nucleotide as 5-hydroxymethyl-2′-deoxycytidine (hmdC). hmdC constitutes 0.6% of total nucleotides in Purkinje cells, 0.2% in granule cells, and is not present in cancer cell lines. hmdC is a constituent of nuclear DNA that is highly abundant in the brain, suggesting a role in epigenetic control of neuronal function.

...read moreread less

2,558 citations

"Consistent decrease in global DNA m..." refers background in this paper

...DNA hydroxymethylation is a newly described epigenetic modification derived from the oxidation of methylated cytosines by ten-eleven translocation (TET) enzymes (Kriaucionis and Heintz, 2009; Tahiliani et al., 2009)....
[...]

Journal Article•DOI•

Linking DNA methylation and histone modification: patterns and paradigms

[...]

Howard Cedar¹, Yehudit Bergman¹•Institutions (1)

Hebrew University of Jerusalem¹

01 May 2009-Nature Reviews Genetics

TL;DR: Relationships between DNA methylation and histone modification have implications for understanding normal development as well as somatic cell reprogramming and tumorigenesis.

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Abstract: Both DNA methylation and histone modification are involved in establishing patterns of gene repression during development. Certain forms of histone methylation cause local formation of heterochromatin, which is readily reversible, whereas DNA methylation leads to stable long-term repression. It has recently become apparent that DNA methylation and histone modification pathways can be dependent on one another, and that this crosstalk can be mediated by biochemical interactions between SET domain histone methyltransferases and DNA methyltransferases. Relationships between DNA methylation and histone modification have implications for understanding normal development as well as somatic cell reprogramming and tumorigenesis.

...read moreread less

2,108 citations

"Consistent decrease in global DNA m..." refers background in this paper

...Methylation of CpG di-nucleotides is catalyzed by DNAmethyltransferases (Dnmts), disrupts the binding of transcription factors and recruits proteins known as methylCpGebinding domain proteins (MBDs) that are associated with chromatin compaction and gene silencing (Cedar and Bergman, 2009)....
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