A team of researchers from the Institute for Basic Science (IBS) in South Korea has made an important discovery that could change the way we understand Alzheimer’s disease.
They found that an enzyme called SIRT2 plays a key role in memory problems linked to the condition. Their work adds to growing evidence that not just neurons but also other brain cells, called astrocytes, are deeply involved in the disease.
For many years, Alzheimer’s was mainly linked to damage in neurons—the cells that send messages in the brain. But more recent research shows that astrocytes, once believed to be just “helper cells,” do more than just support neurons. These star-shaped cells are now known to take an active role in brain functions, including memory.
In Alzheimer’s disease, one of the main features in the brain is the buildup of amyloid-beta plaques. These sticky clumps form between brain cells and are believed to be one cause of memory loss.
When astrocytes detect these plaques, they try to clean them up. To do this, they “eat” the plaques in a process called autophagy and then break them down through something called the urea cycle.
However, while this cleanup process sounds helpful, it comes with a serious downside. As the plaques are broken down, astrocytes start making too much of a brain chemical called GABA. In small amounts, GABA is useful—it helps to calm brain activity.
But in large amounts, it can slow down brain signals too much, leading to memory problems. On top of that, the same process also creates a toxic substance called hydrogen peroxide (H2O2), which can kill brain cells and speed up brain damage.
The IBS researchers wanted to understand which enzymes were responsible for making too much GABA in Alzheimer’s brains. Their goal was to find a way to block this harmful process without interfering with the good work that astrocytes still do.
They used a range of techniques, including microscopic imaging and brain activity tests, to study brain tissue from mice and humans with Alzheimer’s disease.
They discovered that two enzymes—SIRT2 and ALDH1A1—are strongly linked to the extra GABA production. SIRT2, in particular, was found in higher amounts in both mouse models of Alzheimer’s and in brain tissue from human patients who had died with the disease.
To test their theory, the team blocked SIRT2 in the mice. The results were mixed. On the one hand, the mice had better short-term memory in simple tests like the Y-maze. On the other hand, their spatial memory—used to remember places—didn’t improve. This suggests that stopping SIRT2 helped a little, but not enough to fix all the memory issues.
Interestingly, while blocking SIRT2 lowered GABA levels, it didn’t stop the production of hydrogen peroxide. This means that even though some memory symptoms improved, the brain cells might still be dying due to ongoing damage from H2O2.
This shows how complex Alzheimer’s disease is. There may not be one single cause, but rather several problems happening at the same time.
The big breakthrough here is that researchers can now look at the effects of GABA and hydrogen peroxide separately.
Until now, scientists used MAOB inhibitors to block both GABA and hydrogen peroxide at once. But this new discovery allows them to study these two chemicals one by one and better understand how each contributes to brain damage and memory loss.
Director C Justin Lee, who led the study, explained that this could open up more precise ways to treat Alzheimer’s in the future. While SIRT2 itself might not become a drug target—since it doesn’t stop all brain damage—it points scientists in a new direction.
By understanding how astrocytes change in Alzheimer’s and how to control that change, researchers could one day design treatments that slow or stop memory loss more effectively.
In summary, the study shows that SIRT2 and ALDH1A1 are two important enzymes behind the harmful effects of reactive astrocytes in Alzheimer’s disease.
Blocking SIRT2 reduces GABA levels and improves short-term memory, but it doesn’t stop all the damage, because hydrogen peroxide continues to be made. This helps researchers better understand the different pieces of Alzheimer’s and could lead to smarter, more targeted treatments in the future.
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The research findings can be found in Molecular Neurodegeneration.
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