Summary: Researches use an epigenetic approach to correct synaptic dysfunction in the brain associated with memory loss. The findings could help to restore memory function in those with Alzheimer’s and other neurodegenerative diseases.
Source: University at Buffalo.
Research published today (Jan. 22) in the journal Brain reveals a new approach to Alzheimer’s disease (AD) that may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.
The team, led by University at Buffalo scientists, found that by focusing on gene changes caused by influences other than DNA sequences — called epigenetics — it was possible to reverse memory decline in an animal model of AD.
“In this paper, we have not only identified the epigenetic factors that contribute to the memory loss, we also found ways to temporarily reverse them in an animal model of AD,” said senior author Zhen Yan, PhD, a SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB.
The research was conducted on mouse models carrying gene mutations for familial AD — where more than one member of a family has the disease — and on post-mortem brain tissues from AD patients.
AD is linked to epigenetic abnormality
AD results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.
The epigenetic changes in AD happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline, Yan said. A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.
“We found that in Alzheimer’s disease, many subunits of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory,” Yan said.
The researchers found that the loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification, which is elevated in AD. They saw this both in the animal models they studied and in post-mortem tissue of AD patients.
Yan explained that histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell’s transcriptional machinery.
“This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits,” Yan said.
Potential drug targets
Understanding that process has revealed potential drug targets, she said, since repressive histone modification is controlled or catalyzed by enzymes.
“Our study not only reveals the correlation between epigenetic changes and AD, we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors,” Yan said.
The AD animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.
“When we gave the AD animals this enzyme inhibitor, we saw the rescue of cognitive function confirmed through evaluations of recognition memory, spatial memory and working memory. We were quite surprised to see such dramatic cognitive improvement,” Yan said.
“At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.”
The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
Epigenetic advantage
Brain disorders, such as AD, are often polygenetic diseases, Yan explained, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but many genes.
“An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function,” she explained.
“We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function did contribute to cognitive decline in Alzheimer’s disease,” Yan concluded. “If many of the dysregulated genes in AD are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”
Funding: The study was funded by a $2 million National Institutes of Health grant focused on novel treatment strategies for AD.
Other UB co-authors are Yan Zheng; Aiyi Liu; Zi-Jun Wang, PhD; Qing Cao, PhD; Lin Lin; Kaijie Ma; Freddy Zhang; Jing Wei, PhD; Emmanuel Matas, PhD and Jia Cheng, PhD. Additional co-authors are Guo-Jun Chen of Chongqing Medical University, PhD, and Xiaomin Wang, MD, PhD., of the Beijing Institute for Brain Disorders, Capital Medical University.
Source: Ellen Goldbaum – University at Buffalo
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease” by 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, and Zhen Yan in Brain. Published January 22 2019.
doi:10.1093/brain/awy354
[cbtabs][cbtab title=”MLA”]University at Buffalo”It May Be Possible to Restore Memory Function in Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 22 January 2019.
<https://neurosciencenews.com/alzheimers-memory-function-10609/>.[/cbtab][cbtab title=”APA”]University at Buffalo(2019, January 22). It May Be Possible to Restore Memory Function in Alzheimer’s. NeuroscienceNews. Retrieved January 22, 2019 from https://neurosciencenews.com/alzheimers-memory-function-10609/[/cbtab][cbtab title=”Chicago”]University at Buffalo”It May Be Possible to Restore Memory Function in Alzheimer’s.” https://neurosciencenews.com/alzheimers-memory-function-10609/ (accessed January 22, 2019).[/cbtab][/cbtabs]
Abstract
Inhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease
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.
