Right now, there is no treatment that can meaningfully stop or slow the progression of Alzheimer’s disease. But what if scientists could tap into genetics to reveal the key to stopping memory loss in its tracks? That’s what scientists from University at Buffalo claimed to have achieved in an experiment on mice.
For the study, scientists used a breed of mice genetically engineered to have an inherited type of Alzheimer’s. They focused their efforts on epigenetics—the idea that genes can be turned on and off depending on lifestyle and environmental factors. No one really knows why some people get Alzheimer’s and others do not, but we do know that genes inherited from our parents and environmental risk factors, like smoking, obesity or even old age itself, determine whether a brain is susceptible to Alzheimer’s, and even whether plaques and tangles that accumulate in the brains of Alzheimer’s patients lead to symptoms like memory loss. Some people have the beta-amyloid protein plaques, yet never go on to develop the disease—and that, according to researchers, is due to epigenetics.
“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 [Alzheimer’s disease],” said senior author Zhen Yan, Ph.D., a professor at the Jacobs School of Medicine and Biomedical Sciences at University of Buffalo.
According to the study, published in the journal Brain, scientists were able to pinpoint the epigenetic factor related to memory loss. They linked the loss of glutamate receptors, which help cells communicate and are crucial to memory and learning, to memory loss.
“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.
A lack of glutamate receptors was traced to a process called repressive histone modification, which is elevated in Alzheimer’s, and confirmed in the animals they studied and post-mortem tissue of Alzheimer’s patients.
“This AD-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits,” said Yan.
The key discovery was that histone modification is controlled by a certain enzyme. So researchers injected mice with that enzyme three times.
“When we gave the [Alzheimer’s] 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 to the mouse memory lasted for a week. Next, researchers plan to experiment with a longer-lasting inhibitor.
Most importantly, the researchers stressed that approaching Alzheimer’s as having a number of causes is key to unlocking how it happens in the first place.
“An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function,” Yan 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,” she concluded. “If many of the dysregulated genes in [Alzheimer’s] are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”