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A new approach to treating Alzheimer’s disease may make it possible to eventually reverse memory loss, a new study shows.

When researchers focused on gene changes that epigenetics—rather than DNA sequences—cause, it was possible to reverse memory decline in mice.

“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,” says Zhen Yan, professor in the physiology and biophysics department at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo and senior author of the paper in Brain.

Scientists conducted the research 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.

Dramatic cognitive decline

Both genetic and environmental risk factors, such as aging, cause Alzheimer’s disease, researchers say. The combination causes epigenetic changes that then lead to gene expression changes, but scientists aren’t sure how.

The epigenetic changes in Alzheimer’s disease happen primarily in the later stages, when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline, Yan says. 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 says.

Repressive histone modification, which is elevated in Alzheimer’s disease, leads to glutamate receptors loss. Researchers saw this both in the animal models and in human patients’ post-mortem tissue.

“We were quite surprised to see such dramatic cognitive improvement.”

Histone modifiers change the structure of chromatin, which controls how genetic material gains access to a cell’s transcriptional machinery, Yan says.

“This AD-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 reveals potential drug targets, she says, since enzymes control or catalyze repressive histone modification.

“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 says.

Longer-lasting benefits

Researchers injected the mice 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 says. “At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.”

The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are longer-lasting.

Alzheimer’s and other brain disorders are often polygenetic diseases, Yan says, involving many genes, with each causing a modest impact. An epigenetic approach is advantageous because epigenetic processes control not just one gene but many genes.

“An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function,” she says.

“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 AD are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”

Additional coauthors are from the University at Buffalo, Chongqing Medical University, and the Beijing Institute for Brain Disorders, Capital Medical University. The National Institutes of Health supported the work.

Source: University at Buffalo