New Approach to Alzheimer’s May Reverse Memory Loss

In the study published in the journal Brain, the researchers found that by focusing on gene changes caused by influences other than DNA sequences — called epigenetics — it was possible to reverse memory decline in animal models of Alzheimer’s.

“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,” says Yan, senior author on the study.

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 disease results from both genetic and environmental risk factors, such as aging, which combine to result in epigenetic changes, leading to gene expression changes, but little is known about how that occurs.

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, 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,” she says.

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.

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

“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,” she notes.

Understanding that process has revealed potential drug targets, Yan adds, since repressive histone modification is controlled or catalyzed by enzymes.

“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,” she says.

The Alzheimer’s animals were injected three times with compounds designed to inhibit the enzyme that controls repressive histone modification.

“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,” 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 thus longer lasting.

Brain disorders, such as Alzheimer’s, are often polygenetic diseases, Yan explains, where many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she says, because epigenetic processes control many genes instead of just one.

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

“If many of the dysregulated genes in Alzheimer’s are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”

The study was funded by a $2 million National Institutes of Health grant focused on novel treatment strategies for Alzheimer’s disease.

Other co-authors from Yan’s laboratory in the Department of Physiology and Biophysics are:

• Yan Zheng, PhD, former visiting scholar
• Aiyi Liu, former master’s student
• Zi-Jun Wang, PhD, postdoctoral fellow
• Qing Cao, PhD, postdoctoral fellow
• Wei Wang, research scientist
• Lin Lin, former master’s student
• Kaijie Ma, research scientist
• Freddy Zhang, research assistant
• Jing Wei, PhD, former postdoctoral fellow
• Emmanuel Matas, PhD, former postdoctoral fellow
• Jia Cheng, PhD, former doctoral student

Other co-authors are:

• Xiaomin Wang, MD, PhD, of the Beijing Institute for Brain Disorders, Capital Medical University
• Guo-Jun Chen, MD, PhD, of Chongqing Medical University