A new approach to Alzheimer's disease (AD) may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages. In a paper published today in Brain, a team, led by University at Buffalo scientists, found that by focusing epigenetics it was possible to reverse memory decline.
"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, Ph.D.
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.
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. "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.
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 added.
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.
The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.