Enzymes play an important role in cognitive function. Enzymes are biological catalysts. They’re responsible for accelerating chemical reactions.
What role do enzymes play in #aging and cognitive function?
According to new research in laboratory mice by UC San Francisco scientists have discovered that loss of an #enzyme that modifies gene activity to promote brain regeneration may be partly responsible for age-related cognitive decline. When age related cognitive decline starts is still debatable, however the effects of age related cognitive decline are well known.
Age related cognitive decline is responsible for:
- Memory loss
- Lack of focus and attention to details
- You become more compulsive (no wonder why infomercials target the elderly).
More serious diseases such as Alzheimer’s disease is also a result of age related cognitive decline. When scientists restored the enzyme to youthful levels, it showed to improve memory in healthy adult mice. Researchers are hoping the same results will transfer to humans. If it does, new therapies could become available to combat age related cognitive decline and diseases.
The vascular systems of two mice are connected surgically using a technique called parabiosis. This allowed researchers at the UCSF lab of Saul Villeda to observe that the infusion of blood from young mice into older mice caused brain rejuvenation. The older mice began showing improved signs in learning and memory. When the process was reversed, the infusion of blood from old mice into young mice was shown to cause premature cognitive decline in the younger mice.
The next step for the lab was searching for which specific biological molecules in the blood and the brain are responsible for bestowing the benefits of youth or the damage caused by aging.
A post-doctoral researcher in the lab by the name of Geraldine Gontier, Ph.D, discovered the key biological molecule while infusing young blood into the old mice. The molecule is called #Tet2. Tet2 goes into the hippocampus, the part of the brain responsible for memory and learning. As the brain ages it produces less of the Tet2 molecule which results in the decline in the brain’s ability to regenerate. “At first I didn’t believe it,” Gontier said. “I did the experiment again and again to make sure that it was right. But it became clear that some circulating factor in the blood is able to change the level of Tet2 in the brain.”
What is Tet2?
Tet2 is a type of cellular enzyme known as an epigenetic regulator. It makes specific chemical genome annotations to various regions of DNA that changes the activity of many different genes. When the T2t becomes mutated, it plays an important role in the development of age related diseases such as cardiovascular disease, stroke, and cancers.
As T2t declined in the aging mice’s hippocampus the epigenetic tags on DNA did as well. Epigenetic tags have a direct influence on DNA. This discovery by Gontier and colleagues was an important one because they discovered which tags specifically declined. The genes that were associated with #neurogenesis (the ability to produce new brain cells during adulthood) were found to have declined. This was remarkable because Villeda’s team studied the declining of brain cells closer and they discovered it closely resembled the age-related loss of Tet2 expression.
Being good scientists, Villeda’s team used a method called RNAi to block the Tet2 activity in the hippocampi in the mice in order to directly test if T2t reduction in aging caused cognitive decline. RNA interference (RNAi) is a biological process in which RNA molecules inhibit gene expression or translation, by neutralizing targeted mRNA molecules. Utilizing this method it allowed the researchers to find out that as the Tet2 molecule declined so did the birth of new neurons. In other words the Tet2 molecule plays a role in the development of new neurons! As a result the animals had extremely poor performance much like that of the older mice in tests for learning and memory.
Before any cognitive decline becomes detectable, the diminishing of the birth of new neurons starts in early adulthood of the mouse’s hippocampus. The next step for the researchers was to investigate if it’s possible to restore neurogenesis and to potentially prevent the inception of cognitive decline later in life. They planned to do this by boosting the Tet2 levels in the adult hippocampus.
Testing their hypothesis
The researchers caused the over expression of Tet2 in the hippocampus through the use of custom-designed viruses to test their hypothesis. Boosting the levels of Tet2 not only increased the epigenetic DNA tagging but it also restored the brains ability for neurogenesis to more vigorous levels. The researchers discovered that there were no significant differences in tests that involved learning and memory in comparison to the untreated mice. However they showed improvement in their memory of places.
This was an exciting discovery for Villeda. “This was amazing because it’s like improving memory in a healthy, 30-year-old human. I always assumed that because there are no overt cognitive impairments in middle-aged mice, we wouldn’t be able to improve their brain function, but here we see that, no, you can improve cognition to make it better than normal.”
Gontier’s hard work had finally paid off. “This finding is exciting on many levels. I’ve spent my entire Ph.D. and now my postdoc trying to understand how the brain ages and how can we can reverse it. And in this study, we find that one molecule, Tet2, is able to rescue regenerative decline and enhance some cognitive functions in the adult mouse brain.”
Though the results look promising, Villeda does caution that the role of Tet2 levels in the improvement of learning and memory in the mouse brain is still a mystery. It is also questionable if these results will be replicable in humans. Adult neurogenesis’ existence remains a topic of debate, which is why the same benefits seen in mice may not be possible in humans. Villeda does believe there are many features to the brain’s regenerative abilities, and neurogenesis is one of them, and probably not the only one being impacted by altering Tet2 levels.
“In our study we found that removing Tet2 from the hippocampal stem cells that give birth to new neurons caused some cognitive impairment, but removing it from the whole hippocampus caused even more. That suggests that this is about more than just stem cells. This molecule is driving changes throughout the whole brain structure.” Villeda said. “I think of neurogenesis as a signpost of regeneration in the brain, but ultimately I think that it’s changes to the neurons themselves—preventing synapse loss, boosting plasticity—that are going to improve cognition. One of our next big steps is to catalogue exactly what’s happening, both at a genetic level and at a neural level, in mice who’ve had this treatment.”