Scientists identify critical enzymes for astrocytic GABA production in Alzheimer’s disease

A research team at the Institute for Basic Science (IBS) has 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. "When we inhibited the astrocytic expression of SIRT2 in AD mice, we observed partial recovery of memory and reduced GABA production," quoted Mridula BHALLA, the lead author of the study and a post-doctoral researcher at IBS. "While we expected reduced GABA release, we found that only short-term working memory (Y-maze) of the mice was recovered, and spatial memory (NPR) was not. This was exciting but also left us with more questions."

SIRT2 participates in the last step of GABA production, while H₂O₂ is produced earlier in the process. It is therefore possible that H₂O₂ is continuously produced and released by the cells even in the absence of SIRT2. "Indeed, we found that inhibition of SIRT2 continued H₂O₂ production, indicating that neuronal degeneration might continue even though GABA production is reduced," says Director C Justin LEE.

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.

Director C. Justin LEE emphasized the importance of these findings, stating:

"So far, we have been using MAOB inhibitors in AD research, which block the production of H₂O₂ as well as GABA. By identifying enzymes SIRT2 and ALDH1A1 downstream to MAOB, we can now selectively inhibit GABA production without affecting H₂O₂, which would allow us to dissect the effects of GABA and H₂O₂ and study their individual roles in disease progression."

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.