A groundbreaking study by an international research team has revealed new insights into the mechanisms behind memory decline in dementia patients. The researchers also proposed a novel treatment strategy that could potentially restore memory function by targeting specific brain proteins linked to memory impairment.
On Monday, Dr. Chang Jun Lee, director of the Center for Cognition and Sociality at the Institute for Basic Science (IBS), and postdoctoral researcher Dr. Mridula Bhalla announced their team’s discovery. The researchers identified the protein Sirtuin 2 (SIRT2), which is expressed in brain astrocytes, as playing a crucial role in regulating the production of neurotransmitters associated with memory loss.
Astrocytes, star-shaped non-neuronal cells, comprise over half of all brain cells. These cells are essential for coordinating neuronal signal transmission and maintaining stable brain function. However, in conditions such as Alzheimer’s disease or brain inflammation, astrocytes increase in both number and size.
Many scientists believe these cells trigger inflammatory responses early in disease progression and are deeply involved in the onset and advancement of neurodegeneration.
The research team also confirmed the presence of the urea cycle—a process that detoxifies ammonia—in both liver cells and brain astrocytes. They found that putrescine, an intermediate metabolite, is produced in astrocytes when this cycle is active. Putrescine then leads to the excessive production of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) through monoamine oxidase-B (MAO-B).
This overproduction of GABA suppresses brain signal transmission, contributing to memory decline. In addition, hydrogen peroxide—a reactive oxygen species produced alongside GABA—can damage neurons and worsen Alzheimer’s symptoms.
To counter this process, the researchers focused on SIRT2 as a potential regulator of GABA production. SIRT2 plays a role in the final stage of the GABA production pathway. The team conducted experiments to inhibit SIRT2 at the genetic level in astrocytes or to suppress its activity through drug treatments.
The results were promising: GABA production in astrocytes decreased by nearly half, and the inhibitory effect on neurons was reduced by approximately 30 to 40 percent.
To determine whether SIRT2 inhibition could lead to actual memory recovery, the team conducted maze experiments to assess the mice’s ability to remember and navigate new paths. The results showed that impaired short-term memory was restored to near-normal levels.
Dr. Lee commented, “This research opens new possibilities for alleviating memory decline in Alzheimer’s dementia by regulating astrocyte metabolic pathways. We believe SIRT2 could become a key target for selectively controlling GABA production, paving the way for more precise dementia treatments.”
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