Scientists at the Massachusetts Institute of Technology (MIT) have been working on a potential new treatment for Alzheimer’s disease. They are honing in on the genetics involved, hoping to hijack enzymes to do the job.
There are genes that turn on to help us make new memories.
It’s been shown in the past that people need specific genes turned on to make new memories. These genes are unsurprisingly turned off in many Alzheimer’s patients. It’s speculated that the inhibition of this gene has to do with the memory loss seen in Alzheimer’s disease.
A special enzyme helps regulate the activity of memory-making genes
Dr. Li-Huei Tsai is one of the lead researchers for the study and also the director of MIT’s Picower Institute for Learning and Memory. Her previous work in 2007 revealed that inhibiting an enzyme known as HDAC reversed memory loss in experimental mice. They hope to use this knowledge and develop a drug recovering memory loss in people with Alzheimer’s disease.
What is this HDAC enzyme?
HDAC is an enzyme that deals with gene regulation. It takes our DNA and packs the cords tightly into condensed packages using special proteins called histones. These histones serve as a spool so DNA can be wound tightly around it, almost like sewing thread. The resulting structure is called chromatin, which is tightly packaged DNA that cannot be expressed into proteins for function.
How HDAC affects memory loss in Alzheimer’s patients
Though HDAC is involved in gene silencing all over the body, it was in the research team’s immediate interest that it silences memory-forming DNA. There was scientific evidence that a specific form, HDAC2, was found in high levels in brains of Alzheimer’s patients.
The researchers realized that if they could block this enzyme’s activity, they might potentially be able to keep those memory-making genes on. They wondered if this could help reverse the symptoms and memory loss seen in Alzheimer’s disease.
Running into obstacles with blocking HDAC
Sounds simple enough, but the task comes with a challenge. Most of the HDAC inhibitors that we have today also block another form of the enzyme known as HDAC1. Unfortunately, not only does HDAC1 have nothing to do with making memories, but it also is very important for the body to make white and red blood cells. Because the inhibitors are blocking both forms of the enzyme, patients end up getting a lot of toxic side effects from the treatment.
We need to find a way to target HDAC2 while sparing HDAC1. Tsai and her team put the task upon themselves to find this protein of the future. How did they do this?
Finding ways to specifically block HDAC2 without wreaking havoc everywhere else in the body
The team first took samples of brains from those who had already passed away. Analyzing the gene expression in these samples, she identified twenty-eight brain with high HDAC2 levels and 35 brains with low levels. Analyzing a huge array of other genes, they were able to identify over 2000 more genes that seemed to correlate with the level of HDAC2. This correlation suggests that these genes could potentially be linked to the enzyme in question.
They found over 2000 genes that are linked to high levels of HDAC2.
The team carefully picked through their massive list of 2000 genes related to HDAC2. Based on their extensive knowledge of gene functions, they zeroed in on three genes of interest. They subjected these 3 genes to additional testing to see how they relate to HDAC2 specifically. The results of these tests found that a gene known as Sp3 was a vital enabler for the activity of the HDAC2 enzyme.
Sp3 gene was perfectly correlated with high levels of HDAC2.
Researchers hoped that they could somehow manipulate Sp3 to change levels of HDAC2. But first, they had to prove that the two were in fact correlated to each other. The researchers went back to study the brains of the deceased and found that the gene levels of HDAC2 and Sp3 were almost perfectly correlated.
Using Sp3 in mice to bring back recover memory making abilities.
It was time to see if they can manipulate gene expression of Sp3 and cause a change in HDAC2 enzyme levels. Using laboratory mice who had problems with memory, Tsai’s team deactivated Sp3. They found this blockage of Sp3 recovered memory-making ability of the mice.
How did researchers manipulate genes in their experiment?
To block Sp3, researchers use cutting-edge gene technology involving RNA molecules. These molecules have the exact genetic code to complement the code found on the Sp3 gene. Because they are complementary, the two bind to each other and physically block the gene from being expressed. Ultimately this causes Sp3 to be non-functional. They refer to these special mice as “knockdown mice”, meaning they were able to “knock-down” the gene in question using the engineered RNAs.
So it works in mice. What does this mean for using it in patients?
Unfortunately, this method of blocking genes only works great in a mouse model. In order to block Sp3 in humans, the scientists needed to figure out another way. They began to explore chemical molecules and small proteins that could achieve this same Sp3-blocking effect.
Researchers are already working on a protein form to block Sp3 in humans.
The cutting-edge team has made a lot of progress in that respect already. They’ve already figured out what section of the HDAC2 enzyme binds to the Sp3 gene. If they manipulate the brain cells to produce a mass quantity of that specific fragment of HDAC2, the fragments actually bind up all the available Sp3. This results in disabled HDAC2 enzymes and thus, a release of genes in charge of forming memories.
This protein fragment is even better than any of the available HDAC inhibitors we have today
The great thing about this fragment was how it was so targeted for only HDAC2, and not other forms of the enzyme. Because it doesn’t affect HDAC1, it's likely that this fragment would spare the person from the toxicities that come with the alternative HDAC inhibitors that we have today.
What’s keeping this fragment from hitting our pharmacies and curing Alzheimer’s disease?
The fragment used in this study has a length of 90 amino acids, which unfortunately is too big to be an effective drug. The team is working to find a smaller fragment that can still provide the same effect. If that fails, they want to search for a chemical that could possibly break the interactions between Sp3 and HDAC2.
Dr. Tsai and her team continue to work hard to find a drug target they can use in human patients.
While working more on blocking Sp3 activity, Tsai also has turned to the drawing board. She hopes to explore other genes within their list of 2000 showing correlations with HDAC2. This is the best way they might find even more drug targets in the future. She also says that the team will explore the role of these enzymes in other psychiatric diseases such as posttraumatic stress disorder.