A new research has suggested that new drugs may be possible to reverse the memory loss that occurs in Alzheimer’s disease by selectively blocking the ability of the HDAC2 enzyme to interfere with the communication between brain cells. Previous attempts to target HDAC2 have not been successful because the drugs that were used also interfered with other functions of the enzyme, producing toxic side effects.
Now, study has shown that blocking a molecule called sp3 that connects with HDAC2 might be a way to stop them both from disrupting synaptic function, or the communication between brain cells that is essential for memory. A report on the study, led by researchers from the MIT in Cambridge, is published in the journal Cell Reports.
Senior author Prof. Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT, says that they believe that HDAC2 is a main regulator of genes that control memory and that because its levels are raised in Alzheimer’s disease, it blocks the function of those genes.
“If we can remove the blockade by inhibiting HDAC2 activity or reducing HDAC2 levels,” Prof. Tsai explains, “then we can remove the blockade and restore expression of all these genes necessary for learning and memory.”
Alzheimer’s disease is the most common form of dementia, a progressive brain-wasting condition that slowly diminishes people’s ability to think, remember, reason, and make decisions. As the symptoms get worse, people are no longer able to hold a conversation and respond to what is happening around them. Experts do not yet know exactly what causes Alzheimer’s disease, but they say that it could be due to several factors that occur differently in different people.
Although it can affect younger people, Alzheimer’s disease is more common among older people aged 60 or above. Around 5 million people are considered to be living with Alzheimer’s disease in the United States, and this number will increase to 14 million by 2050. The new study concerns the disruption of a biological process called synaptic plasticity, which is thought to be essential for learning and memory.
Research on what happens at synapses has revealed that they are “plastic” and not fixed as the joints in electronic circuits are. Life-extending protein could treat Alzheimer’s and Parkinson’s Synaptic plasticity is defined as a biological process whereby synapse evolves over time, depending on specific patterns of activity.
The synaptic changes interfere with various properties, including the strength of communication between brain cells, which affects memory. Prof. Tsai has been researching the role that enzymes called HDACs play in memory loss for over a decade. In 2007, she found out that blocking HDAC activity in mice could reverse memory loss. There are around a dozen types of HDAC in humans.
HDACs affect memory by altering histones, which are the proteins that help to package DNA into a structure called chromatin. The effect of HDAC is to enhance chromatin, which, in turn, decreases the expression of some genes in the DNA. In later research, Prof. Tsai found that a particular HDAC in humans called HDAC2 blocked some genes that are essential for memory, and that levels of the enzyme are higher in people with Alzheimer’s and also in mice with the disease.
Compounds that inhibit HDAC2 have already been tested, but most of these have side effects. For example, they interfere with HDAC1, which is important for cell proliferation, especially in white and red blood cells.
Therefore, Prof. Tsai and colleagues want to figure out how to target only the activity of HDAC2 that interferes with memory by searching for proteins that help the enzyme to connect with the relevant genes.
Gene expression data from post-mortems of people who did not have Alzheimer’s disease – some whose brains had high and some whose had low levels of HDAC2 – helped the team to find more than 2,000 genes that might be involved with HDAC2 activity.
Using other information that they already had about how the genes behave with HDAC2, the team whittled down the candidates to three. Further tests on these three led them to Sp3, a “transcription factor” molecule that helps HDAC2 to alter chromatin and block the memory genes on the DNA.
Gene expression data from post-mortem samples taken from brains of people who died with Alzheimer’s disease revealed a strong link between levels of HDAC2 and Sp3. The researchers then showed that reducing sp3 expression in a mouse model of Alzheimer’s disease restored the animals’ ability to have long-term memories.
Our findings indicate that targeting the HDAC2-Sp3 complex could enhance cognitive function without interfering with HDAC2 function in other processes.” The team also found a molecule that might act as a basis for developing a drug that prevents sp3 from connecting with HDAC2 to free the memory genes. They showed that the molecule does not interfere with cell proliferation, as some other HDAC inhibitors do.
Prof. Tsai says that there is more work to do – such as finding a smaller version of the molecule – before they can test on a suitable experimental drug candidate. She also wishes to find out how many other genes might be connecting with HDAC2, which could lead to other drug targets.