Alzheimer’s Disease, a form of age-related dementia, is a chronic degenerative disorder of the brain, primarily affecting people aged 65 and older. While it starts out with minor issues such as forgetting recent events, it eventually causes victims to experience language difficulties, moodiness, inability to find their way around and loss of motivation. Eventually, victims lose control over their bodily functions.
Ultimately, the disease is fatal, with death occurring within nine years of diagnosis. Although there are no treatments or cures, a recent discovery made by researchers at the Massachusetts Institute of Technology indicates a way that will eventually enable doctors to prevent and possibly reverse the memory loss caused by Alzheimer’s.
Medical science is unclear on the causes of Alzheimer’s. There are a number of hypothesis suggesting that genetics may play a role, as well as toxins entering the brain due to failure of the blood-brain barrier. The mechanics of the disease are well understood, however.
The symptoms are due to two factors: (1) plaque buildup as the result of extra-cellular deposits of a substance known as amyloid beta and (2) the dysfunction of “tau” proteins, which provide stability to cell structure. Up to this point, the majority of research in this area has been concentrated on reducing the buildup of these plaques. However, it is not understood how and why this plaque buildup causes memory loss. Although medications have been developed that are able to clear these deposits, they are ineffective in helping Alzheimer’s patients in regaining their cognitive abilities.
Dr. Li-Huei Tsai, a member of the research team and co-author of the study, theorized that another factor was involved. In the course of earlier research, Dr. Tsai had discovered that a group of enzymes, known as histone deacetylases (HDACs), play an important role in cognitive function. In simple terms, certain HDACs can affect DNA, causing it to “close up,” preventing genes from communicating.
In experiments on lab mice exhibiting symptoms of Alzheimer’s, Dr. Tsai and her colleagues found that one particular HDAC – identified as HDAC2 – was plentiful in the hippocampus, the region in the brain associated with memory formation. HDAC2 was found to be “clinging” to genes involved in the control of synaptic control, the connections between neurons that build or weaken in response to new stimuli.
This in turn blocks the genes’ ability to carry out their function. Tsai noted, “With such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions.”
When the researchers shut off HDAC in the hippocampi of the test mice, these genes were able to resume their jobs. As a result, synaptic density began to increase once more and normal cognitive function was eventually restored. The problem has been to find some way to disable the action of HDAC2 by itself. Up until now, science has been unable to find anything that specifically targets HDAC2.
The recent study has identified a protein known as Sp3, which is also a “transcription factor.” This substance also plays a role in the communication between DNA and RNA – and as it turns out, assists HDAC2 in causing synaptic damage in the brain. By using fragments of HDAC2, researchers were able to connect with Sp3 in the brains of lab mice, using an experimental technique known as “gene knockdown,” a method of disabling gene communication.
These results, as promising as they seem, do not mean that the methods used on lab mice would work with human subjects. However, the study has revealed what appears to be at the root of Alzheimer’s-related memory loss, giving medical scientists a target at which to train pharmaceutical weapons – and illuminates a path to the development of medications that could one day make Alzheimer’s Disease a relic of the past.
The MIT study appeared in the August 8th issue of Cell Reports.