According to a preclinical study, it might be possible to restore memory in Alzheimer's disease



[ad_1]

BUFFALO, NY – Research published today (January 22) in the journal Brain reveals a new approach to Alzheimer's disease that could eventually help address memory loss, characteristic of the disease at a advanced stage.

The team, led by scientists at the University of Buffalo, discovered that by focusing on genetic modifications caused by influences other than DNA sequences, called epigenetics, it was possible to reverse the decline of memory in an animal model of AD.

"In this article, we have not only identified the epigenetic factors that contribute to memory loss, we have also found ways to temporarily reverse them in an animal model of AD," said lead author Zhen Yan, PhD, Distinguished Professor in the Department of Physiology and Biophysics of the Faculty of Medicine and Biomedical Sciences Jacobs of UB.

The research was conducted on murine models carrying genetic mutations for familial AD – where more than one family member has the disease – and on post-mortem brain tissue from AD patients.

AD is linked to an epigenetic anomaly

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

Epigenetic changes in Alzheimer's disease occur mainly in the late stages, when patients are unable to retain the newly acquired information and exhibit the most dramatic cognitive decline, Yan said. The loss of glutamate receptors, essential for learning and short-term memory, is one of the leading causes of cognitive decline.

"We found that in Alzheimer's disease, many subunits of glutamate receptors in the frontal cortex are negatively regulated, disrupting excitatory signals, thereby impairing working memory," Yan said.

The researchers discovered that the loss of glutamate receptors is the result of an epigenetic process called repressive modification of the histone, which is high in Alzheimer's disease. They found it in both the animal models studied and in the post-mortem tissues of AD patients.

Yan explained that histone modifiers alter the structure of chromatin, which controls the access of genetic material to the transcription mechanism of a cell.

"This alteration of the abnormal histone-related AD is what represses gene expression, decreasing glutamate receptors, resulting in loss of synaptic function and memory deficits," he said. said Yan.

Potential drug targets

Understanding that this process has revealed potential drug targets, she said, because the repressive modification of histone is controlled or catalyzed by enzymes.

"Our study not only reveals the correlation between epigenetic changes and AD, but we also found that we can correct cognitive dysfunction by targeting epigenetic enzymes to restore glutamate receptors," said Yan.

AD animals were injected three times with compounds designed to inhibit the enzyme that controls the repressive modification of the histone.

"When we administered this enzyme inhibitor to AM animals, we found that recovery of cognitive function was confirmed by evaluations of recognition memory, spatial memory, and working memory. to see such dramatic cognitive improvement, "said Yan.

"At the same time, we witnessed the recovery of expression and function of glutamate receptors in the frontal cortex."

The improvements lasted a week; Future studies will focus on developing compounds that penetrate the brain more efficiently and last longer.

Epigenetic advantage

Brain disorders, such as Alzheimer's disease, are often polygenetic diseases, many genes are involved and each gene has a modest impact. An epigenetic approach is advantageous, she said, because epigenetic processes control not just one gene but several genes.

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

"We have provided evidence showing that abnormal epigenetic regulation of glutamate receptor expression and function contributes to the cognitive decline of Alzheimer's disease," Yan concluded. "If many dysregulated genes in AD 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 grant from the National Institutes of Health, focused on new strategies for treating AD.

Other co-authors of UB are Yan Zheng; Aiyi Liu; Zi-Jun Wang, PhD; Qing Cao, PhD; Lin Lin; Kaijie Ma; Freddy Zhang; Jing Wei, PhD; Emmanuel Matas, PhD and Jia Cheng, PhD. The other co-authors are Guo-Jun Chen from Chongqing Medical University, PhD, and Xiaomin Wang, MD, PhD. From Beijing Institute of Brain Disorders, Capital Medical University.

PHOTO: http: // www.buffalo.edu /new/releases /2019 /01 /013.html

Warning: AAAS and EurekAlert! are not responsible for the accuracy of the news releases published on EurekAlert! contributing institutions or for the use of any information via the EurekAlert system.

[ad_2]
Source link