29-05-2025
Breakthrough Alzheimer's study finds enzyme that ties brain inflammation to memory loss
In a major breakthrough, scientists have identified a little-known enzyme as a key trigger in the chain reaction behind cognitive decline.
Researchers at South Korea's Institute for Basic Science (IBS) discovered that SIRT2, previously overlooked in the context of astrocytic GABA production, may help untangle the specific effects of degenerative molecules linked to Alzheimer's disease.
The study sheds new light on astrocytes, once considered mere support cells, revealing their active role in brain dysfunction by overproducing the inhibitory neurotransmitter GABA in response to amyloid-beta plaques, a defining feature of the condition.
Although astrocytes help clear these plaques, the process sets off a harmful cascade, absorbing amyloid-beta through autophagy and break it down via the urea cycle as outlined in previous studies.
This breakdown results in excessive GABA production, which suppresses brain activity and impairs memory. It also generates hydrogen peroxide (H₂O₂), which speeds up neurodegeneration.
The IBS research team focused on identifying the specific enzymes to uncover the cause behind the excessive production of GABA, aiming to neutralize their effects without disrupting normal brain activity.
Using a combination of molecular analysis, microscopic imaging, and electrophysiological techniques, the researchers pinpointed two enzymes, SIRT2 and ALDH1A1, as central to the surge in GABA levels within astrocytes affected by Alzheimer's disease.
Notably, elevated levels of SIRT2 were observed in astrocytes of both a widely used Alzheimer's mouse model and in brain tissue from human patients diagnosed with the disease.
'When we inhibited the astrocytic expression of SIRT2 in AD mice, we observed partial recovery of memory and reduced GABA production,' Mridula Bhalla, the lead author of the study and a post-doctoral researcher at IBS, said.
'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 is involved in the final step of GABA production, whereas hydrogen peroxide (H₂O₂) is generated earlier in the process. This suggests that H₂O₂ may continue to be produced and released by astrocytes even when SIRT2 is absent.
'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 pinpointing SIRT2 and ALDH1A1 as downstream targets, researchers can now selectively suppress GABA production without altering H₂O₂ levels — a critical breakthrough that enables the independent study of GABA and H₂O₂ in neurodegeneration.
Director C. Justin LEE said that by identifying enzymes SIRT2 and ALDH1A1 could selectively inhibit GABA production without affecting H2O2.
'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,' he said.
Although SIRT2 itself may not be an ideal drug target given its limited influence on neurodegeneration, the findings lay critical groundwork for developing more targeted therapies to regulate astrocytic reactivity in Alzheimer's disease.
The study has been published in the journal Molecular Neurodegeneration.
