Yan and her team used an epigenetic approach to restore memory function in an animal model of Alzheimer's Disease.
Credit: Douglas Levere/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."
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.
Journal Reference:
- 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, 2019 DOI: 10.1093/brain/awy354
Courtesy: ScienceDaily
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