A team, led by University at Buffalo scientists, reveal 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. What they did was correct the synaptic dysfunctions in the brain involved in memory loss, using an epigenetic approach. The findings were published very recently on January 22, 2019 in the journal Brain.
Zhen Yan, PhD, senior author of the study, and a SUNY Distinguished Professor in the Department of Physiology and Biophysics in the Jacobs School of Medicine and Biomedical Sciences at UB, said:
“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.”
The study was conducted on mouse models carrying gene mutations for familial AD (where more than one member of a family has the disease) as well as on post-mortem brain tissues from AD patients. What the researchers found is 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. Yan explained:
“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.”
Epigenetic Abnormality And Alzheimer’s Disease
AD is linked to epigenetic abnormality. How? AD occurs as a result of both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes. This then leads to gene expression changes, but little is yet known about how that happens. These epigenetic changes occur primarily in the later stages – the point at which a person is unable to retain recently learned information and is exhibiting the most dramatic cognitive decline.
Yan explains that a key reason for the cognitive decline is the loss of glutamate receptors. They are critical to learning and short-term memory. The loss of glutamate receptors is the result of an epigenetic process known as repressive histone modification. The process involves these histone modifiers changing the structure of chromatin, which controls how genetic material gains access to a cell’s transcriptional machinery. She said:
“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…This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits.”
Repressive histone modification is controlled or catalyzed by enzymes and therefore the process has revealed potential drug targets. Yan says:
“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.”
How did they find this? The study involved the AD animals being injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification. Yan said:
“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… At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.”
The improvements are only temporary. They lasted for one week. Now they are focusing their future studies on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
She has confidence in an epigenetic approach because epigenetic processes control not just one gene but many genes, and brain disorders (like AD) are often polygenetic diseases – where many genes are involved and each gene has a modest impact. She explains:
“An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function…We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function did contribute to cognitive decline in Alzheimer’s disease. 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.”