Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease

Mastroeni, Diego; McKee, Ann C.; Grover, Andrew; Rogers, Joseph; Coleman, Paul D.

doi:10.1371/journal.pone.0006617

Cited by 268 publications

(185 citation statements)

References 25 publications

Supporting

Mentioning

170

Contrasting

Unclassified

Order By: Relevance

“…Recently, a study in a pair of monozygotic twins revealed the importance of DNA methylation in a discordant case of AD (Mastroeni et al 2009). The AD twin had significantly lower amounts of DNA methylation in the neocortex.…”

Section: Discussionmentioning

confidence: 99%

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

Walker

LaFerla

Oddo

et al. 2012

AGE

View full text Add to dashboard Cite

With aging and Alzheimer's disease (AD), there is an increased sensitivity to stress along with declines in the memory-associated neurotrophin brainderived neurotrophic factor in AD. We have replicated this aging phenotype in cultured neurons from aged mice despite being grown in the same environmental conditions as young neurons. This led us to hypothesize that age-related differences in epigenetic acetylation and methylation of histones are associated with age-related gene regulation. We cultured hippocampal/ cortical neurons from the 3xTg-AD mouse model and from non-transgenic mice to quantify single cell acetylation and methylation levels across the life span. In non-transgenic neurons, H3 acetylation was unchanged with age, while H4 acetylation decreased with age of the donor. Compared to nontransgenic neurons, 3xTg-AD neurons had higher levels of H3 and H4 acetylation beginning at 4 months of age. In contrast to non-transgenic neurons, 3xTg-AD neurons increased acetylation with age; 3xTg-AD neurons also responded differently to inhibition of histone deacetylases at an early age. Importantly, treatment of non-transgenic neurons with the AD peptide Aβ also elevated levels of acetylation. We also examined the repressive function of histone H3 lysine 9 (H3K9) methylation. H3K9 methylation increased with age in non-transgenic neurons, which was amplified further in 3xTg-AD neurons. The dominant effect of higher H3K9 methylation was supported by lower Bdnf gene expression in non-transgenic and 3xTg-AD mice. These data show that the epigenetic states of non-transgenic and 3xTg-AD brain neurons are profoundly different and reversible, beginning at 4 months of age when the first memory deficits are reported.

show abstract

Section: Discussionmentioning

confidence: 99%

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

Walker

LaFerla

Oddo

et al. 2012

AGE

View full text Add to dashboard Cite

show abstract

“…87 AD patients have been further characterized by a decrease in brain SAM levels, 88 and, concomitant with this, temporal neocortex neuronal nuclei were found to be hypomethylated in a patient with AD compared to his non-AD monozygotic twin. 89 5hmC, which exists at high levels within the brain, has also been implicated in AD, inferring a potential involvement of demethylation with neurodegeneration. 90 In accordance with this possibility, a single nucleotide polymorphism in the gene encoding TET1 (rs5030882) was reported to be associated with late-onset AD.…”

Section: Aberrant Methylation In Noncancerous Diseasesmentioning

confidence: 99%

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

Johnson

Akman²,

Calimport³

et al. 2012

Rejuvenation Research

328

218

View full text Add to dashboard Cite

DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

show abstract

“…Three catalytically active enzymes, DNA methyltransferase1 (DNMT1), DNMT3a, and DNMT3b, have been identified for the establishment and maintenance of DNA methylation patterns in mammalian cells. Pathologically altered DNA methylation has been described in various cancers (13,14), and its role is starting to be revealed in many other diseases such as multiple sclerosis (15), Alzheimer's disease (16), and systemic lupus erythematosus (17). However, the role of different DNMTs in regulation of skeletal muscle atrophy program remains completely unknown.…”

mentioning

confidence: 99%

DNA Methyltransferase 3a and Mitogen-activated Protein Kinase Signaling Regulate the Expression of Fibroblast Growth Factor-inducible 14 (Fn14) during Denervation-induced Skeletal Muscle Atrophy

Tajrishi

Shin

Hetman

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Levels of Fn14 are increased in skeletal muscle on denervation. Results: Denervation represses Dnmt3a levels and increases MAPK signaling in skeletal muscle to increase gene expression of Fn14. Conclusion: Promoter hypomethylation and MAPKs play critical roles in induction of Fn14 levels in denervated muscle. Significance: Increasing Dnmt3a or blocking MAPK signaling can be an important approach to repress Fn14 levels and denervation-induced muscle atrophy.

show abstract

Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease

Cited by 268 publications

References 25 publications

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease

DNA Methyltransferase 3a and Mitogen-activated Protein Kinase Signaling Regulate the Expression of Fibroblast Growth Factor-inducible 14 (Fn14) during Denervation-induced Skeletal Muscle Atrophy

Contact Info

Product

Resources

About