In a recent study, researchers found a new approach to Alzheimer’s disease (AD) that may eventually make it possible to reverse memory loss, a hallmark of the disease in its late stages.
They 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.
The research was led by University at Buffalo scientists.
AD 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 AD happen primarily in the later stages when patients are unable to retain recently learned information and exhibit the most dramatic cognitive decline.
A key reason for the cognitive decline is the loss of glutamate receptors, which are critical to learning and short-term memory.
Previous research has 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 current study 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.
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 the post-mortem tissue of AD patients.
In addition, they found ways to temporarily reverse the condition in an animal model of AD. They corrected the cognitive dysfunction by targeting the epigenetic enzymes to restore glutamate receptors.
The improvements lasted for one week; future studies will focus on developing compounds that penetrate the brain more effectively and are thus longer-lasting.
The team says abnormal epigenetic regulation of glutamate receptor expression and function can 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.
One author of the study is Zhen Yan, Ph.D., a SUNY Distinguished Professor.
The study is published in the journal Brain.
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