Essential Enzyme May Hold Key to Fighting Memory Loss in Alzheimer's

Scientists have discovered that in Alzheimer’s disease, certain brain cells called astrocytes overproduce a substance called GABA, which can impair memory. They identified two enzymes, SIRT2 and ALDH1A1, that help with this overproduction. By blocking the action of SIRT2 in mice with Alzheimer’s, GABA levels returned to normal and memory improved, which could pave the way for new, more targeted treatments.

Astrocytes are very important cells in the brain. They help maintain chemical balance, control communication between neurons, and protect the brain from damage. In Alzheimer’s disease (AD), a condition that causes loss of memory and other cognitive functions, these cells change dramatically in shape and function.

One of these changes is the overproduction of GABA, a substance that normally helps calm brain activity but that in excess can cause problems, especially in diseases like Alzheimer’s. However, we still don’t fully understand how astrocytes produce this GABA, especially which enzymes are involved in this process.

GABA in astrocytes can come in two main forms: it can be absorbed from the surrounding environment or it can be produced internally from other substances, such as glutamate or putrescine (a small molecule derived from amino acids).

It was already known that putrescine could be converted to GABA by an enzyme called MAOB, but another alternative pathway involving an enzyme called DAO has also been discovered. These two pathways convert putrescine to GABA by different pathways, with MAOB being the longest and most complex.

The MAOB pathway has several steps. First, putrescine is converted to a substance called N-acetyl-putrescine with the help of an enzyme called PAT. This substance is then oxidized by MAOB, creating a chemical intermediate.

This intermediate needs to be converted to N-acetyl-GABA by an enzyme in the ALDH (aldehyde dehydrogenase) family, and researchers suspect that either ALDH2 or ALDH1A1 are responsible. Finally, N-acetyl-GABA is converted to GABA by a deacetylase enzyme, possibly one of the sirtuin family, mainly SIRT2.

Sirtuins are enzymes involved in several cellular functions, including protein control and cellular aging. Among them, SIRT2 has attracted attention for being involved in other neurodegenerative diseases, such as Parkinson's and Huntington's.

Therefore, scientists decided to investigate whether SIRT2 is also involved in this final process of GABA production in astrocytes, especially in Alzheimer's disease.

To study this, researchers from the University of Science and Technology, Korea, analyzed which genes were active in astrocytes grown in the laboratory and in models of Alzheimer's, both in mice and humans.

They looked for genes that encode enzymes involved in this process, such as SIRT2 and ALDH1A1. They used a series of techniques to see if these enzymes were actually involved in GABA production, by directly measuring the levels of GABA and the intermediate substances in astrocytes. They also looked at the effects of inhibiting these enzymes, either with drugs or genetic manipulation.

The results showed that both SIRT2 and ALDH1A1 are important for GABA production in astrocytes.

This figure shows how two enzymes, SIRT2 and ALDH1A1, are essential for astrocytes (the brain’s supporting cells) to convert putrescine (a natural compound) into GABA, a chemical messenger that normally calms brain activity but, in excess, can disrupt memory in Alzheimer’s. In panels A and D, we see the timeline of the experiments: first, they treated lab-grown astrocytes with putrescine, and then they either added drugs to block SIRT2 (such as EX527 or AGK2) or used a genetic method to “turn off” SIRT2 or ALDH1A1 in the cells. In images B and E, color-coded astrocytes show where GABA is: in red, and cells in green (GFAP) or pink (mCherry) indicate which ones received the genetic block. Finally, in graphs C and F, the “violin” shows how much color (i.e., GABA) appears in each condition. The widest part of the violin indicates where most of the cells are, and the lines in the center mark the median of the group. The “p” numbers above the graphs tell us whether the difference between the groups is statistically significant: the smaller the “p”, the more certain we are that blocking SIRT2 or ALDH1A1 actually reduces GABA production. When SIRT2 was blocked, GABA production went down, but production of another toxic substance, hydrogen peroxide (H2O2), did not change. This is important because hydrogen peroxide has been linked to cell death in the brain.

In addition, in both the brains of mice with Alzheimer’s and in tissue from human patients, SIRT2 was most active in astrocytes. When the scientists specifically turned off the SIRT2 gene in just the mice’s astrocytes, GABA levels returned to normal and the animals improved on memory tests.

This study is the first to clearly show that SIRT2 plays a specific role in the overproduction of GABA in astrocytes during Alzheimer’s. It also confirms that ALDH1A1 helps in this process.

These findings are important because they indicate new targets for the development of treatments that can regulate GABA production in the brain without affecting other substances, such as hydrogen peroxide, which could be crucial to treating neurodegenerative diseases more effectively and safely.

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SIRT2 and ALDH1A1 as critical enzymes for astrocytic GABA production in Alzheimer’s disease

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

Molecular Neurodegeneration. 20, Article number: 6 (2025) 

DOI: 10.1186/s13024-024-00788-8

Abstract:

Alzheimer’s Disease (AD) is a neurodegenerative disease with drastically altered astrocytic metabolism. Astrocytic GABA and H2O2 are associated with memory impairment in AD and synthesized through the Monoamine Oxidase B (MAOB)-mediated multi-step degradation of putrescine. However, the enzymes downstream to MAOB in this pathway remain unidentified. Using transcriptomics analysis, we identified two candidate enzymes, Aldehyde Dehydrogenase 1 family member A1 (ALDH1A1) and Sirtuin 2 (SIRT2) for the steps following MAOB in the astrocytic GABA production pathway. We used immunostaining, metabolite analysis and electrophysiology, both in vitro and in vivo, to confirm the participation of these enzymes in astrocytic GABA production. We checked for the presence of SIRT2 in human AD patients as well as the mouse model APP/PS1 and finally, we selectively ablated SIRT2 in the astrocytes of APP/PS1 mice to observe its effects on pathology. Immunostaining, metabolite analysis, and electrophysiology recapitulated the participation of ALDH1A1 and SIRT2 in GABA production. Inhibition of SIRT2 reduced the production of astrocytic GABA but not H2O2, a key molecule in neurodegeneration. Elevated expression of these enzymes was found in hippocampal astrocytes of AD patients and APP/PS1 mice. Astrocyte-specific gene-silencing of SIRT2 in APP/PS1 mice restored GABA production and partially improved memory function. Our study is the first to identify the specific role of SIRT2 in reactive astrogliosis and determine the specific pathway and metabolic step catalyzed by the enzyme. We determine the partial, yet significant role of ALDH1A1 in this process, thereby highlighting 2 new players the astrocytic GABA production pathway. Our findings therefore, offer SIRT2 as a new tool to segregate GABA from H2O2 production, aiding future research in neurodegenerative diseases.