Scientists have shown that it is possible to reverse memory loss in mice by blocking the activity of a specific protein – the enzyme HDAC2. This discovery may pave the way for the development of new drugs to limit cognitive decline in Alzheimer's disease patients.
HDAC2 works by blocking the genes that are required to form new memories. Previous research has shown that people diagnosed with Alzheimer's have unusually high levels of this enzyme, and scientists believe that targeting it with drugs could hold promise for improving cognitive impairment associated with the condition, including memory loss.
Until now however, they had not succeeded in developing drugs to block HDAC2's activity. Most of the treatments researchers had tested so far also blocked another enzyme of the same family, HDAC-1.
This could lead to toxic side effects as HDAC1 is involved in cell proliferation, in particular in the production of white and red blood cells.
Targeting the right enzyme
In a study now published in the journal Cell Reports, scientists have looked for a way to more specifically target HDAC2. They worked to identify proteins that help this enzyme bind to genes required for memory formation.
To do so, they analysed postmortem brain samples taken from people who did not have Alzheimer's disease, including 28 brains with high HDAC-2 levels and 35 with low levels. They identified 2,000 genes whose levels closely matched HDAC2 levels, suggesting they might be associated.
Next, they isolated three of those genes for further testing, based on what they already knew about how they worked. They found out that one of these, Sp3, is necessary for HDAC2 to block memory-linked genes.
To test what these findings would mean when it comes to reversing memory loss, the researchers explored what would happen if they lowered Sp3 levels in a mouse model of Alzheimer's disease.
They found that blocking the Sp3 gene restored the mice's ability to form long-term memories, suggesting that it would be an interesting therapeutic target.
For this approach to be useful for potentially restoring memory function in human patients, scientists would need to develop a drug in the form of a small protein or chemical compound that would block the interaction between HDAC2 and Sp3.
The study is a positive development, and the scientists have already identified the section of the HDAC2 protein that binds to Sp3, facilitating future drug development. However, more research will be needed before this work can find a concrete application in humans.
Lead author Li-Huei Tsai, from the MIT, now hopes to investigate in greater depths some of the other genes that were found to correlate with HDAC2, to try and identify other drug targets.