A team led by scientists from the University at Buffalo (UB) has found that focusing on gene changes caused by influences other than DNA sequences — referred to as epigenetics — makes it possible to reverse memory decline in the animal model of Alzheimer’s disease (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 UB team conducted their research on mouse models carrying gene mutations for familial AD, which are cases in which more than one member of a given family has the disease. Post mortem brain tissues from human AD patients was also studied.
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.
While it is known that these epigenetic changes occur from environmental and genetic risk factors such as aging which lead to gene expression changes, it is not known exactly how the loss of glutamine receptors occurs. However, the team at UB team was able to discover that this phenomenon can be attributed to 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.
This discovery has led to potential drug targets.
“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.”
Administration of the drug resulted in improvements which lasted for one week. Future studies will focus on developing medication which are more effective at penetrating the brain, which would make them have a longer-lasting effect.
The study was published in the journal Brain on January 22.