Correlation Engine 2.0
Clear Search sequence regions


Sizes of these terms reflect their relevance to your search.

Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of ageing and neurodegeneration. Here we found that, in the late-stage familial Alzheimer's disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9me2) and euchromatic histone methyltransferases EHMT1 and EHMT2 were significantly elevated in the prefrontal cortex, a key cognitive region affected in Alzheimer's disease. Elevated levels of H3K9me2 were also detected in the prefrontal cortex region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9me2 at glutamate receptors was increased in prefrontal cortex of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in prefrontal cortex and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9me2 enrichment at genes involved in neuronal signalling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder. © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Citation

Yan Zheng, Aiyi Liu, Zi-Jun Wang, Qing Cao, Wei Wang, Lin Lin, Kaijie Ma, Freddy Zhang, Jing Wei, Emmanuel Matas, Jia Cheng, Guo-Jun Chen, Xiaomin Wang, Zhen Yan. Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer's disease. Brain : a journal of neurology. 2019 Mar 01;142(3):787-807

Expand section icon Mesh Tags

Expand section icon Substances


PMID: 30668640

View Full Text