Dementia victims could have their memories restored, suggests a new study.
Researchers say a new approach to Alzheimer’s may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.
The findings, published in the journal Brain, suggest 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 Alzheimer’s.
Senior author Professor Zhen Yan, of University at Buffalo in the US, 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 Alzheimer’s Disease.”
The research was conducted on mouse models carrying gene mutations for familial Alzheimer’s – where more than one member of a family has the disease – and on post-mortem brain tissues from Alzheimer’s patients.
Alzheimer’s results from both genetic and environmental risk factors, such as ageing, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.
Prof Yan said the epigenetic changes in Alzheimer’s happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline.
She said a key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.
Prof Yan said: “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 Alzheimer’s.
They saw this both in the animal models they studied and in post-mortem tissue of Alzheimer’s patients.
Prof Yan explained that histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell’s transcriptional machinery.
She said: “This Alzheimer’s-linked abnormal histone modification is what represses gene expression, diminishing glutamate receptors, which leads to loss of synaptic function and memory deficits.”
Understanding that process has revealed potential drug targets, she said, since repressive histone modification is controlled or catalyzed by enzymes.
Prof Yan said: “Our study not only reveals the correlation between epigenetic changes and Alzheimer’s, we also found we can correct the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors.”
The Alzheimer’s animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.
Prof Yan said: “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.
“At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.”
The improvements lasted for a week, but future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
Prof Yan explained that brain disorders, such as Alzheimer’s, are often polygenetic diseases, where many genes are involved and each gene has a modest impact.
She said an epigenetic approach is advantageous, because epigenetic processes control not just one gene but many genes.
She added: “An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function.
“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 Alzheimer’s are normalised by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behaviour.”
By Stephen Beech
