Restoring memory function in Alzheimer’s disease may now be possible

Washington: A study now finds that a new approach to Alzheimer’s disease (AD) may eventually make it possible to reverse memory loss, a hallmark of the disease in its later stages.

The study was published in the journal Brain.

The research, led by University at Buffalo, scientists found 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.

Speaking about it, senior author Zhen Yan 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 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.
Yan further added, “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.”

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.

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.

Understanding that process has revealed potential drug targets since repressive histone modification is controlled or catalysed by enzymes, she said.

“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 study saw AD animals being injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.

On being given enzyme inhibitors, researchers saw the rescue of cognitive function that was confirmed through evaluations of recognition memory, spatial memory and working memory. “At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex,” 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, Yan said.