Today’s research has open new doors for the treatment of Alzheimer’s disease. The research has now made possible to reverse one of the major manifestation of Alzheimer’s disease in a later stage that is memory loss. Researchers at the University at Buffalo observed that other than focusing on the changes in DNA sequences, observing other factors for change in a gene (gene expression)- epigenetics- made possible to reverse memory loss in an animal model of Alzheimer’s disease.
Zhen Yan, lead author, Ph.D., a SUNY Distinguished head 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 memory loss, we also found ways to temporarily reverse them in an animal model of AD.”
The research was experimented on mouse models who were the carriers of familial Alzheimer’s disease and on the autopsy brain tissues of AD patients. These familial mice are the ones whose at least one family member is also affected by the same disease.
Epigenetic Abnormality Plays a Key Role in Alzheimer’s disease
Both genetic and environmental factors like aging can contribute to Alzheimer’s disease. Though everyone knows AD can cause changes in gene expression, little is known about the cause which triggers it.
According to Yan, in AD the epigenetic changes usually occur at last stages where the patient is unable to process the new information and shows a tremendous decline in the memory loss rate. This is just because of the loss of functioning of the glutamate receptors which are responsible for learning and processing new information.
Yan said: “We found that in Alzheimer’s disease, many subunits of glutamate receptors in the frontal cortex are down-regulated, disrupting the excitatory signals, which impairs working memory.”
According to the new finding, the main cause behind this loss of receptors is an epigenetic process named repressive histone modification. In Alzheimer’s disease patients, this process works abnormally. It was observed in both the experimental models. In repressive histone modification, a mutation in the structure of chromosome leads to an abnormal functioning on how the genetic material connects to the process of transcription.
“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.
The Birth to Potential Drug Targets
After a keen observation of the process, researchers have come up with potential drug targets as the repressive histone modification is catalyzed by enzymes. According to Yan, “Our study not only reveals the correlation between epigenetic changes and Alzheimer’s disease, but we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors.”
The models were injected three times with the substances which control the functioning of an enzyme that influences the process of 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 results were only effective for one week. Researchers are currently working on developing substances which will prove to be more efficient and effective in penetrating the brain as well as will be long-lasting.
The advantage of Epigenetic Process
According to Yan, many of the brain diseases including Alzheimer’s disease is a polygenetic disease which means that it is controlled by more than one gene. All of these genes influence the disorder to some extent. Yan explained that the epigenetic process is a positive one as it does not only direct one gene but also controls other genes too.
She said, “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 further 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. 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.”