A groundbreaking study conducted by a team of researchers at the Institute for Basic Science (IBS) has unveiled crucial enzymes tied to memory loss in Alzheimer’s disease. Under the leadership of Director C Justin LEE, this research provides profound insights into how specific brain cells, known as astrocytes, contribute to cognitive decline through the overproduction of an inhibitory neurotransmitter called GABA. Traditionally viewed as mere support systems for neurons, astrocytes have emerged as active players in brain function and dysfunction. In Alzheimer's patients, these cells react to amyloid-beta plaques, leading to a cascade of harmful processes that impair memory.

The investigation focused on understanding which enzymes were responsible for excessive GABA production, aiming to selectively block its detrimental effects without disrupting other essential brain activities. Through advanced techniques such as molecular analysis, microscopic imaging, and electrophysiology, the scientists identified two key enzymes—SIRT2 and ALDH1A1—that play pivotal roles in GABA overproduction within Alzheimer’s-affected astrocytes. Notably, elevated levels of SIRT2 were observed not only in mouse models commonly used for Alzheimer's research but also in post-mortem human brains affected by the disease. According to Mridula BHALLA, the lead author of the study, inhibiting SIRT2 in Alzheimer's mice resulted in partial memory recovery and reduced GABA levels, although certain types of memory improvement were more pronounced than others.

This discovery opens new avenues for therapeutic strategies targeting Alzheimer's disease. By pinpointing SIRT2 and ALDH1A1 as critical components downstream from MAOB inhibitors, researchers can now selectively inhibit GABA production without affecting hydrogen peroxide (H2O2), another byproduct linked to neurodegeneration. This separation allows for a deeper understanding of the individual roles of GABA and H2O2 in the progression of Alzheimer's. Although SIRT2 may not serve as a direct drug target due to its limited impact on neurodegeneration, this research underscores the importance of precise approaches aimed at controlling astrocytic reactivity. Such advancements bring hope for future treatments capable of mitigating the devastating effects of Alzheimer's disease while promoting healthier brain functions.