Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease

Cao, Qing; Wang, Wei; Williams, Jamal B; Yang, Fan; Wang, Zijun; Yan, Zhen

doi:10.1126/sciadv.abc8096

Cited by 60 publications

(56 citation statements)

References 73 publications

(103 reference statements)

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“…The time spent around the correct hole (T1) and all the other incorrect holes (T2) was recorded. The spatial memory index (T1/T2) was calculated as previously described (Cao et al, 2020 ; Wang et al, 2018 ). For repeated measurements, visual cues were changed before training.…”

Section: Methodsmentioning

confidence: 99%

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Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

et al. 2021

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Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD‐like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.

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Section: Methodsmentioning

confidence: 99%

“…Differences in gene expression levels between samples were defined with at least 1.2‐Fold Change (FC) and p < 0.05. GO annotation was carried out as we previously described (Cao et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

et al. 2021

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“…Furthermore, in mouse models of AD, H3K9me2 levels are elevated in the prefrontal cortex, and inhibition of the methyltransferases for this mark rescued deficits in recognition memory, working memory, and spatial memory [195]. Similarly, H3K4me3 levels are increased in the prefrontal cortex in AD mouse models, and pharmacological inhibition of this mark leads to recovery of synaptic function and memory impairments [196]. Increases in DNA 5mC and 5hmC levels have been reported in the hippocampus of AD patients [197], though 5mC was decreased in the hippocampus of a mouse AD model with no changes in 5hmc [198].…”

Section: Epigenetics In Alzheimer's Disease-related Memory Lossmentioning

confidence: 97%

Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer’s Disease

Maity

Farrell

Navabpour

et al. 2021

IJMS

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Epigenetic mechanisms, which include DNA methylation, a variety of post-translational modifications of histone proteins (acetylation, phosphorylation, methylation, ubiquitination, sumoylation, serotonylation, dopaminylation), chromatin remodeling enzymes, and long non-coding RNAs, are robust regulators of activity-dependent changes in gene transcription. In the brain, many of these epigenetic modifications have been widely implicated in synaptic plasticity and memory formation. Dysregulation of epigenetic mechanisms has been reported in the aged brain and is associated with or contributes to memory decline across the lifespan. Furthermore, alterations in the epigenome have been reported in neurodegenerative disorders, including Alzheimer’s disease. Here, we review the diverse types of epigenetic modifications and their role in activity- and learning-dependent synaptic plasticity. We then discuss how these mechanisms become dysregulated across the lifespan and contribute to memory loss with age and in Alzheimer’s disease. Collectively, the evidence reviewed here strongly supports a role for diverse epigenetic mechanisms in memory formation, aging, and neurodegeneration in the brain.

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“…Similarly, a loss of nuclear H3K4me3 mark in hippocampal subregions but not cytoplasmic H3K4me3 mark was found in an AD animal (3×Tg) model, which develops plaques and NFTs [ 103 ]. Similarly, the H3K4m3 mark, as well as specific HMTs, such as KMT2A-D in the PFC nuclear fraction from human AD, was significantly enhanced without affecting H3K27me3 or H3K4me marks [ 104 ]. A similar increase in H3K4me3 and Kmt2a was also found in P301S transgenic Tau mice (PS19) [ 104 ].…”

Section: Alzheimer’s Disease (Ad)mentioning

confidence: 99%

“…Similarly, the H3K4m3 mark, as well as specific HMTs, such as KMT2A-D in the PFC nuclear fraction from human AD, was significantly enhanced without affecting H3K27me3 or H3K4me marks [ 104 ]. A similar increase in H3K4me3 and Kmt2a was also found in P301S transgenic Tau mice (PS19) [ 104 ]. These epigenetic advances provide robust experimental evidence using multiple AD models and suggest that restoring histone methylation’s homeostasis specifically mediated by G9a/GLP and KMT2A-D may perhaps be a potential therapeutic strategy to treat AD-related neurodegenerative disorders.…”

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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Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease

Cited by 60 publications

References 73 publications

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model

Epigenetic Mechanisms in Memory and Cognitive Decline Associated with Aging and Alzheimer’s Disease

Histone Methylation Regulation in Neurodegenerative Disorders

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