Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain

Narayan, Pritika; Lill, Claire L.; Faull, Richard L.M.; Curtis, Maurice A.; Dragunow, Mike

doi:10.1016/j.nbd.2014.11.023

Cited by 111 publications

(77 citation statements)

References 103 publications

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“…Interestingly, histone deacetylase (HDAC) inhibitors have been shown to ameliorate symptoms of cognitive decline and synaptic dysfunction in mouse models of AD 13, 14 and are promising targets for novel human AD treatments 15,16 . Despite this, investigations into global levels of histone acetylation in AD have thus far been inconclusive [17][18][19][20] and no study has taken a . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Introductionmentioning

confidence: 99%

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Marzi

Ribarska

Smith

et al. 2017

Preprint

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Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) -a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding -in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/183541 doi: bioRxiv preprint first posted online 3 Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and memory loss that contributes substantially to the global burden of disease, affecting in excess of 26 million people worldwide 1 . The symptoms of AD are associated with progressive neuropathology in the neocortex, with regions surrounding the entorhinal cortex being particularly affected early in the disease 2 . These neuropathological hallmarks of AD include the extracellular deposition of neurotoxic amyloid-β (Aβ) in the form of amyloid plaques and an accumulation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau 3 . Despite progress in understanding risk factors contributing to AD progression, the mechanisms involved in disease progression are not fully understood and long-term treatments, reversing the cellular disease process in the cortex, are elusive.The...

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Section: Introductionmentioning

confidence: 99%

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Marzi

Ribarska

Smith

et al. 2017

Preprint

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“…Both the amygdaloid pCREB and CBP levels are notably raised by acute ethanol exposure and decreased in rats undergoing withdrawal after chronic ethanol exposure. These findings suggest that changes in CBP levels may be implicated in the dynamic chromatin remodeling in the amygdala caused by acute and chronic ethanol exposures [67] . A key role of histone acetylation was observed in a recent study, in which the hyposensitivity to gamma-aminobutyric acid in the ventral tegmental area during alcohol withdrawal in mice was found to be mediated by HDAC [67] .…”

Section: Impact Of Alcohol On Histone Acetylation/ Deacetylationmentioning

confidence: 82%

“…CBP has an intrinsic HAT activity and, when recruited by CREB, can promote transcriptional activation by acetylating histones [66] . CREB functioning is found to direct the expression of genes associated with alcohol addiction, such as BDNF, neuropeptide Y and activity-regulated cytoskeleton-associated protein (Arc) [67] . NPY mRNA levels were found to be reduced in the amygdala of alcohol-preferring (P) rats compared to alcohol non-preferring (NP) rats, implying that NPY has a role in anxiety-like and alcoholdrinking behaviors [67] .…”

Section: Impact Of Alcohol On Histone Acetylation/ Deacetylationmentioning

confidence: 99%

“…CREB functioning is found to direct the expression of genes associated with alcohol addiction, such as BDNF, neuropeptide Y and activity-regulated cytoskeleton-associated protein (Arc) [67] . NPY mRNA levels were found to be reduced in the amygdala of alcohol-preferring (P) rats compared to alcohol non-preferring (NP) rats, implying that NPY has a role in anxiety-like and alcoholdrinking behaviors [67] . Direct infusion of NPY into the central region of amygdala (CeA) produced anxiolytic effects and reduced alcohol intake in P rats, which is likely increased by CREB phosphorylation in the CeA region of the brain [68,69] .…”

Section: Impact Of Alcohol On Histone Acetylation/ Deacetylationmentioning

confidence: 99%

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Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

Jangra¹,

Sriram²,

Pandey³

et al. 2016

Ann Neurosci

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Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development.

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“…It has been demonstrated that histone acetylation was lower in the temporal lobe of AD patients than in aged controls [21]. However, another study has found increased acetyl and total levels in postmortem AD brains [22]. …”

Section: Histone Acetylation In Admentioning

confidence: 99%

Epigenetic Modification and Its Role in Alzheimer's Disease

et al. 2015

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Alzheimer's disease (AD) is the most common neurodegenerative disease, and its mechanisms have not been clearly elucidated. A large percentage (more than 95%) of cases are late-onset AD without familial traits. Although some genes have been implicated in the pathogenesis and the risk of developing sporadic AD, they only account for the minority of late-onset AD. Recently, accumulating data have suggested a potential role for epigenetic mechanisms in neurodegenerative processes leading to dementia. Alterations in the epigenetic machinery cause aberrant DNA methylation and histone acetylation. Therefore, these changes trigger alterations on the transcriptional level of genes involved in the pathogenesis of AD. In this review, we summarize recent advances in research on AD caused by common epigenetic modification and the potential treatment strategies targeting the epigenetic machinery.

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Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain

Cited by 111 publications

References 103 publications

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

Epigenetic Modification and Its Role in Alzheimer's Disease

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