On Apr. 14, 2025, a research team at the Institute for Basic Science (IBS) in Korea announced they have identified a previously unknown enzyme, SIRT2, that plays a key role in memory loss associated with Alzheimer’s disease (AD).

The study, led by Director C Justin LEE, of the IBS Center for Cognition and Sociality, provides critical insights into how astrocytes contribute to cognitive decline by producing excessive amounts of the inhibitory neurotransmitter GABA.

Astrocytes, once thought to only support neurons, are now known to actively influence brain function. In Alzheimer’s disease, astrocytes become reactive, meaning they change their behavior in response to the presence of amyloid-beta (Aβ) plaques, a hallmark of the disease.

While astrocytes attempt to clear these plaques, this process triggers a harmful chain reaction. First, they uptake them via autophagy (Kim and Chun, 2024) and degrade them by the urea cycle (Ju et al, 2022), as discovered in previous research. However, this breakdown results in the overproduction of GABA, which dampens brain activity and leads to memory impairment. Additionally, this pathway generates hydrogen peroxide (H2O2), a toxic byproduct that causes further neuronal death and neurodegeneration.

The IBS research team set out to uncover which enzymes were responsible for excessive GABA production, hoping to find a way to selectively block its harmful effects without interfering with other brain functions. Using molecular analysis, microscopic imaging, and electrophysiology, the researchers identified SIRT2 and ALDH1A1 as critical enzymes involved in GABA overproduction in Alzheimer’s-affected astrocytes.

SIRT2 protein was found to be increased in the astrocytes of the commonly used AD mouse model as well as in post-mortem human AD patient brains. By identifying SIRT2 and ALDH1A1 as downstream targets, scientists can now selectively inhibit GABA production without affecting H2O2 levels. This is a critical breakthrough because it allows researchers to separate the effects of GABA and H2O2 and study their individual roles in neurodegeneration.

While SIRT2 may not be a direct drug target due to its limited effects on neurodegeneration, this research paves the way for more precise therapeutic strategies aimed at controlling astrocytic reactivity in Alzheimer’s disease. The study was published in Molecular Neurodegeneration and is available under open access.