Age, but Not Amyloidosis, Induced Changes in Global Levels of Histone Modifications in Susceptible and Disease-Resistant Neurons in Alzheimer’s Disease Model Mice

Dyer, Marcus S; Phipps, Andrew J.; Mitew, Stanislaw; Taberlay, Phillippa C.; Woodhouse, Adele

doi:10.3389/fnagi.2019.00068

Cited by 13 publications

(12 citation statements)

References 53 publications

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“…Central to the cell senescence model is that it is not changes in telomere length per se, but rather the subsequent changes in gene expression (epigenetic changes) that play the functional role in cell senescence and in subsequent clinical disease. This is in line with the current emphasis on regulatory rather than coding variables, that is, Shifts in epigenetic expression 102 resulting from the senescence process are gradual and subtle but still cause progressive cell dysfunction. The rate of turnover is surprisingly critical 103 and can be defined and quantified numerically by formula.…”

Section: Genetic and Epigenetic Baseline Effectssupporting

confidence: 75%

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A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment, 1 there are no proven disease-modifying interventions. Despite huge and growing costs of care, 2 a pipeline of candidate drugs, 3 >400 registered trials, 4 tens of thousands of patients, 5 billions of dollars in both US federal 6 and pharmaceutical company investment, 7,8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed 9 in attempts to prevent, slow, or alter the course of the dementias.This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias. 10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015, 11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions.The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications.The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Current dementia modelsAlthough there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias. 12 Over the past century, 13 several models have attained varying degrees of acceptance.Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1).Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors.Until recently, the foremost among such explanations has been amyloid (A ) theory, [14][15][16][17] in various iterations. Other candidates have been tau tangles, 18-20 mitochondrial dysfun...

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Section: Genetic and Epigenetic Baseline Effectssupporting

confidence: 75%

“…Shifts in epigenetic expression resulting from the senescence process are gradual and subtle but still cause progressive cell dysfunction. The rate of turnover is surprisingly critical and can be defined and quantified numerically by formula .…”

Section: Part 2: Summary Of the Modelmentioning

confidence: 99%

A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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“…In contrast, decreased H3K4me3 with no change in H3K27me3 marks at the ANK1 gene locus in postmortem AD brains was reported [ 101 ]. Interestingly, an age-related increase in H3K27me3 was observed in neurofilament (NF)-labeled calretinin-positive interneurons [ 102 ]. However, amyloid plaque deposition and its sequelae failed to alter global H3K27me3 in NF-positive calretinin-labeled interneurons.…”

Section: Alzheimer’s Disease (Ad)mentioning

confidence: 99%

Histone Methylation Regulation in Neurodegenerative Disorders

Basavarajappa

Subbanna

2021

IJMS

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Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.

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“…These post-translational histone modifications are related to AD pathology and of great significance in the development of AD ( 104 ). With regard to the regulators of histone modifications, in APP/PS1 mice, age is associated with the global levels of histone modifications, suggesting that age is one of the main risk factors in the histone modifications of AD ( 105 ). An epigenome-wide association study demonstrates that tau protein affects histone acetylation changes and an altered chromatin structure in AD prefrontal cortices ( 106 ) ( Table 3 ).…”

Section: Histone Modifications In Admentioning

confidence: 99%