Researchers found the reason memory fades due to dementia. A treatment strategy has also emerged, which regulates the metabolic pathway of proteins in the brain involved in memory decline associated with Alzheimer's dementia to restore memory.
Lee Chang-jun, Director General of the Institute for Basic Science (IBS) Cognition and Sociality Research Team, and a research team led by postdoctoral researcher Mridula Bhalla discovered that the protein "sirtuin 2 (SIRT2)" expressed by astrocytes in the brain is a key protein that regulates the production of neurotransmitters that cause memory damage. They also revealed that inhibiting this protein makes it possible to recover short-term memory.
Astrocytes are star-shaped non-neural cells that account for more than half of all brain cells, playing a role in coordinating signaling between neurons and maintaining stable brain function. When diseases such as Alzheimer's or brain inflammation occur, the number and size of astrocytes increase. For this reason, scientists believe that astrocytes induce inflammatory responses from the early stages of the disease and are deeply involved in the onset and progression of neurodegeneration.
The research team discovered in previous studies that a urea cycle that detoxifies ammonia exists not only in the liver but also in astrocytes in the brain. They further found that when the urea cycle operates in astrocytes, it produces putrescine, an intermediate metabolite, which excessively creates the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) through monoamine oxidase-B (MAO-B).
Excessive GABA inhibits signaling in the brain, leading to memory decline. Hydrogen peroxide, an active oxygen species produced alongside GABA, also damages neurons and exacerbates Alzheimer's symptoms.
The research team focused on SIRT2 as a key factor that can regulate GABA production. SIRT2 is a protein involved in the final stage of the GABA generation pathway. The research team conducted experiments to suppress SIRT2 at the gene level in astrocytes or to inhibit its activity using drugs to analyze the effects on GABA production and brain function.
As a result of inhibiting SIRT2 in astrocytes, GABA production in astrocytes decreased by nearly half, and the inhibitory effect on neurons was reduced by about 30% to 40%. Additionally, to confirm whether the inhibition of SIRT2 leads to actual memory recovery, they conducted a maze experiment assessing the ability of mice to remember and navigate new routes, which showed that impaired short-term memory was restored to nearly normal levels.
Lee Chang-jun, Director General of the IBS, noted, "This study suggests the possibility of alleviating memory decline in Alzheimer's dementia by regulating the metabolic pathway of astrocytes. In particular, SIRT2 is a key target that selectively regulates GABA production and is expected to be an effective target for the development of precise dementia treatments."
References
Molecular Neurodegeneration (2025), DOI : https://doi.org/10.1186/s13024-024-00788-8