Gene Expression Switched Off in Alzheimer's
Epigenetics involves external modifications to genes that don’t change the DNA sequence itself. For instance, a boy's genes might suggest he should reach six feet in height, but prolonged malnutrition may shorten this expectation by several inches. External factors (diet) modified the genes so they couldn't fully express themselves. If Alzheimer's follows a similar pattern, then some external modification could alter gene expression to prevent or reverse the disease process. Biochemical groups within cells that can modify the function of proteins and alter the ways genes are expressed are called epigenetic marks. In the study I’m going to talk about today, the scientists set out to investigate the role of a type of mark -- methyl groups -- located in proteins called histones. The addition of methyl groups to histones switches off gene expression. Reversing the process will switch them back on. To figure out how this works, the Buffalo group, together with colleagues from China, used mice that carry gene mutations causing them to develop a disease that closely resembles Alzheimer's in humans. When the scientists looked at brain samples from the prefrontal cortex -- a key area for higher level cognitive processes and working memory -- they found more methyl groups within histones. In older mice that had already developed dementia, there were even higher levels of these marks.The Role of Glutamate
In Alzheimer's patients, epigenetic alterations usually occur in the later stages of the disease because of a loss of glutamate receptors. Glutamate is the brain's major excitatory neurotransmitter. It allows nerve cells to fire electric signals and facilitates communication between neurons where they join with one another at the connections called synapses. This process is key for learning and short-term memory. In the mice, the researchers found a loss of glutamate receptors to be a direct consequence of additional methyl groups. They also found the same phenomenon took place within post-morten human brain tissue they analyzed. Lead scientist Zhen Yan summed up their initial findings: "We found that in Alzheimer's, many sub-units of glutamate receptors in the frontal cortex are downregulated, disrupting the excitatory signals, which impairs working memory. "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.” The next stage of the research was to see if anything could be done to stop this damaging series of events kicked off by methyl group accumulation in histones.Brain Cells Restored to Normal
The researchers found two specific enzymes carry methyl groups to histones, so they injected an inhibitor of these enzymes into the mice. Professor Yan explains what happened next: “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,” she said. “At the same time, we saw the recovery of glutamate receptor expression and function in the frontal cortex.” She concluded by saying, "An epigenetic approach can correct a network of genes, which will collectively restore cells to their normal state and restore the complex brain function. "If many of the disregulated genes in Alzheimer's are normalized by targeting specific epigenetic enzymes, it will be possible to restore cognitive function and behavior.”Not Yet Ready for Prime Time
It wasn't all good news however. The improvements in the mice lasted only seven days. However, the scientists are confident they can improve the therapy and create a far better outcome. Commenting on the study, Tiago Outeiro, Professor of Neurodegeneration at Newcastle University, England, said, "While this study is exciting and promising, it confirms already existing evidence highlighting that epigenetics may be an important player in the complexity of Alzheimer's disease." Judging by some of the other comments made by scientists, it looks like epigenetic research is going to take off in a big way. Whether this will result in a new treatment for human dementia patients is unknown at this time.