Alzheimer’s Breakthrough: Scientists Identify Key Enzyme That Links Brain Inflammation to Memory Loss

SIRT2, an enzyme previously overlooked in astrocytic GABA production, may be crucial for distinguishing the specific effects of degenerative molecules involved in Alzheimer’s disease.

A research team at the Institute for Basic Science (IBS) has discovered that SIRT2, an enzyme previously unknown in this context, plays a key role in memory loss linked to Alzheimer’s disease. The study, led by Director C. Justin LEE of the IBS Center for Cognition and Sociality, offers important insights into how astrocytes contribute to cognitive decline by producing too much of the inhibitory neurotransmitter GABA.

Astrocytes, once believed to only provide support for neurons, are now recognized as active participants in brain function. In Alzheimer’s disease, these cells become reactive, changing their behavior in response to the presence of amyloid-beta (Aβ) plaques, a defining feature of the condition. Although astrocytes work to clear these plaques, the process sets off a harmful chain of events.

They absorb the plaques through autophagy (Kim and Chun, 2024) and break them down via the urea cycle (Ju et al., 2022). This breakdown leads to the excessive production of GABA, which suppresses brain activity and contributes to memory impairment. The same process also produces hydrogen peroxide (H2O2), a toxic byproduct that accelerates neuronal damage and neurodegeneration.

Uncovering the enzymes behind GABA overproduction

To understand what drives this overproduction of GABA, the IBS team aimed to identify the enzymes responsible, with the goal of blocking the negative effects without disrupting other brain functions. Through molecular analysis, microscopic imaging, and electrophysiological techniques, they identified SIRT2 and ALDH1A1 as key enzymes responsible for the elevated GABA levels in astrocytes affected by Alzheimer’s disease.

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.”

H2O2 persists despite reduced GABA

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.

Reference: “SIRT2 and ALDH1A1 as critical enzymes for astrocytic GABA production in Alzheimer’s disease” by Mridula Bhalla, Jinhyeong Joo, Daeun Kim, Jeong Im Shin, Yongmin Mason Park, Yeon Ha Ju, Uiyeol Park, Seonguk Yoo, Seung Jae Hyeon, Hyunbeom Lee, Junghee Lee, Hoon Ryu and C. Justin Lee, 15 January 2025, Molecular Neurodegeneration.
DOI: 10.1186/s13024-024-00788-8

Funding: Institute for Basic Science

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