Increased DNA methylation near TREM2 is consistently seen in the superior temporal gyrus in Alzheimer's disease brain

Smith, Adam R.; Smith, Rebecca G.; Condliffe, Daniel; Hannon, Eilís; Schalkwyk, Leonard C.; Mill, Jonathan; Lunnon, Katie

doi:10.1016/j.neurobiolaging.2016.07.008

Cited by 74 publications

(55 citation statements)

References 29 publications

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“…With regards to candidate gene analysis the most remarkable finding was a negative association between methylation at cg25748868 in TREM2 and WMH (standardized regression coefficient = -11,3, p = 3.9-E03); however, this did not survive Bonferroni correction for multiple testing (a <1.1E-03) and neither did any of the other tested comparisons (full data not shown). WMH load has been consistently associated with AD; TREM2 hypomethylation and overexpression have been previously observed when comparing blood samples of AD and controls, while increased TREM2 methylation and hydroxymethylation have been observed in AD brain [34][35][36][37][38]. Overall it is likely that previously identified associations between cell composition and Parkinson's disease as well as methylation and expression changes in ABCA7, TREM2 and SNCA with AD and SNCA methylation with dementia with Lewy bodies are specific for those conditions and thus not present in our dataset [27,34,[39][40][41].…”

Section: Resultsmentioning

confidence: 82%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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Aim:The present study investigated the link between peripheral DNA methylation (DNAm), cognitive impairment and brain aging. Methods: We tested the association between blood genome-wide DNAm profiles using the Illumina 450K arrays, cognitive dysfunction and brain MRI measures in selected participants of the Whitehall II imaging sub-study. Results: Eight differentially methylated regions were associated with cognitive impairment. Accelerated aging based on the Hannum epigenetic clock was associated with mean diffusivity and global fractional anisotropy. We also identified modules of co-methylated loci associated with white matter hyperintensities. These co-methylation modules were enriched among pathways relevant to β-amyloid processing and glutamatergic signaling. Conclusion: Our data support the notion that blood DNAm changes may have utility as a biomarker for cognitive dysfunction and brain aging. DNA methylation (DNAm) changes have been linked with the pathophysiology of brain aging, Alzheimer's disease (AD) and other types of dementia [1,2]. Considering the relative stability of DNAm and the fact that it is directly modulated by both underlying genetic sequence and environmental exposures it appears as a promising peripheral biomarker for brain-related changes [3]. Peripheral changes in mRNA and proteins that are downstream of DNAm regulation further support this concept [4,5]. Studies have shown differences in blood DNAm when comparing AD subjects with controls [6], but interestingly when looking at specific genes there is little overlap between brain and blood DNAm changes in AD [7,8]. However, a good peripheral biomarker does not have to mirror disease-associated changes in the brain; it could also simply represent a peripheral response to central pathology. At present, there is limited data available on the potential utility of peripheral DNAm as a marker for cognitive decline before the onset of dementia. One study of patients with Type 2 diabetes mellitus who later developed presymptomatic dementia highlighted leukocyte DNAm changes that were comparable to changes identified in blood in AD patients and could thus potentially represent early markers of dementia [9]. Recently DNAm epigenetic clocks have been developed, which provide a measure of epigenetic age, based on DNAm levels at 353 CpG sites [10] and 71 CpG sites [11], respectively. A number of studies have utilized the epigenetic age in blood, based on the DNAm epigenetic clock, to show correlations with cognitive function, white matter hyperintensities (WMH), Parkinson's disease, Down syndrome and all-cause mortality [12][13][14][15][16].

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Section: Resultsmentioning

confidence: 82%

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

et al. 2018

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“…This may also be the case for TREM2, as a recent meta-analysis concluded that increased methylation of the TREM2 promoter region appears to be an invariant feature in the brains of AD patients independently of age and sex [64]. Moreover, this increase in methylation correlates with a higher level of TREM-2 (triggering receptor expressed on myeloid cells 2) activity in the brains of AD patients compared with healthy age-and sexmatched controls [69].…”

Section: Introductionmentioning

confidence: 90%

“…The fact that TREM-2 acts as an ApoE receptor may also be of importance as this allows for an exaggerated effect of the ApoE4 protein in the context of dysfunctional TREM-2 receptors [132]. Moreover, a recent meta-analysis reported that increased methylation of the TREM2 promoter region appears to be an invariant feature in the brains of AD patients independently of age and sex [64]. Moreover, this increase in methylation is associated with a higher level of TREM-2 activity in the brains of AD patients compared with healthy controls [69].…”

Section: Influence Of Trem-2 Elevation In Pmbcsmentioning

confidence: 99%

“…However, while genetics clearly plays a role in AD susceptibility, the vast bulk of cases does not show strong genetic underpinnings [61,62]. Moreover, although common sequence variants in several genes display robust associations with AD susceptibility, evidenced by individual studies and subsequent meta-analyses, collectively, these SNPs only account for approximately a third of attributable risk and the mechanisms underpinning these associations remain undelineated [63]; reviewed by [64].…”

Section: Introductionmentioning

confidence: 99%

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Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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“…; Smith et al . ). Studies of alterations in MAPT DNA methylation in AD are currently inconclusive, with reports of both AD‐associated hypomethylation (Iwata et al .…”

Section: A Role For Dna Modifications In Ad?mentioning

confidence: 97%

Epigenetics and DNA methylomic profiling in Alzheimer's disease and other neurodegenerative diseases

Roubroeks

Smith

Hove

et al. 2017

Journal of Neurochemistry

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Recent studies have suggested a role for epigenetic mechanisms in the complex etiology of various neurodegenerative diseases. In this review, we discuss advances that have been made toward understanding the role of epigenetic processes in neurodegenerative disorders, with a particular focus on Alzheimer's disease, where the most extensive studies have been undertaken to date. We provide a brief overview of DNA modifications, followed by a summarization of studies of DNA modifications in Alzheimer's disease and other neurodegenerative diseases.

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Increased DNA methylation near TREM2 is consistently seen in the superior temporal gyrus in Alzheimer's disease brain

Cited by 74 publications

References 29 publications

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Peripheral DNA Methylation, Cognitive Decline and Brain Aging: Pilot Findings from The Whitehall II Imaging Study

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Epigenetics and DNA methylomic profiling in Alzheimer's disease and other neurodegenerative diseases

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