Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease

Zheng, Yi; Liu, Aiyi; Wang, Zijun; Cao, Qing; Wang, Wei; Lin, Lin; Ma, Kaijie; Zhang, Freddy; Wei, Jing; Matas, Emmanuel; Cheng, Jia; Chen, Guojun; Wang, Xiaomin; Yan, Zhen

doi:10.1093/brain/awy354

Cited by 129 publications

(140 citation statements)

References 70 publications

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“…The present findings lend credence to the emerging story supporting the modifiability of key aspects of glutamate/glutamine metabolism, and, indirectly, the observations by Zheng et al (2019), who found that restoration of the expression of the glutamate receptor (via EHMT1/2 inhibition) reversed cognitive deficits in their FAD mice [1]. A higher circulating level of glutamine might mean that more of the substrate is available for use in the brain during times of stress, acting as a neuroprotectant [5].…”

Section: Resultssupporting

confidence: 86%

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Circulating glutamine and Alzheimer’s disease: a Mendelian randomization study

Adams¹

2019

Preprint

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INTRODUCTIONAlzheimer’s disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent.METHODSA two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain.RESULTSThe results reveal a protective effect of circulating glutamine (inverse-variance weighted method, odds ratio per 1-SD increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02).CONCLUSIONThese findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer’s disease.

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Section: Resultssupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Circulating glutamine and Alzheimer’s disease: a Mendelian randomization study

Adams¹

2019

Preprint

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“…In particular, cHC is characterized by relatively high levels of the trimethylated form of lysine 9 of histone H3 (H3K9me3), while the fHC is enriched for H3K9me2; these H3K9me2/me3 marks repress gene transcription, maintain genome stability (by silencing repetitive DNA elements and transposons), and protect DNA from damage [20,21,[23][24][25][26][27]. Recent studies document that the distributions and/or expression levels of H3K9me2/me3 are altered in the brains of patients and also in models of Alzheimer's disease [26,[28][29][30], Huntington's disease [31], and Rett syndrome [32].…”

Section: Introductionmentioning

confidence: 99%

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

et al. 2020

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Background: Hexanucleotide repeat expansions of the G 4 C 2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results: Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI-or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions: Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.

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“…Recently, Zheng et al (2019) reported a restoration of cognitive function in late-stage familial Alzheimer's disease (FAD) mice with inhibition of euchromatin histone methyltransferases 1 and 2 (EHMT1/2). 1 Doing so reversed histone hypermethylation (H3K9me2) at the promoters of the glutamate receptors and restored their expression. These are important findings that point to the targetability of EHMT1/2 in relation to glutamate receptor biology and, indirectly, possibly to the targetability of glutamate metabolism.…”

Section: Introductionmentioning

confidence: 99%

<p>Circulating Glutamine and Alzheimer’s Disease: A Mendelian Randomization Study</p>

Adams¹

2020

CIA

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Video abstractPoint your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use:https://youtu.be/nvEXdk_hzgcBackground: Alzheimer's disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent.Methods: A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain. Results:The results reveal a protective effect of circulating glutamine against Alzheimer's disease (inverse-variance weighted method, odds ratio per 1-standard deviation increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02).Conclusion: These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer's disease.

show abstract

Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease

Cited by 129 publications

References 70 publications

Circulating glutamine and Alzheimer’s disease: a Mendelian randomization study

Circulating glutamine and Alzheimer’s disease: a Mendelian randomization study

Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice

<p>Circulating Glutamine and Alzheimer’s Disease: A Mendelian Randomization Study</p>

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