Breakthrough Discovery Links Enzyme to Memory Loss in Alzheimer's Disease

Recent research conducted by a team at the Institute for Basic Science (IBS) has unveiled a previously unidentified enzyme, SIRT2, which appears to play a significant role in memory loss associated with Alzheimer's disease (AD). This study offers essential insights into how brain inflammation, particularly through the activation of astrocytes, contributes to cognitive decline by increasing the production of the inhibitory neurotransmitter GABA.

Astrocytes, once considered mere support cells for neurons, are now recognized for their active participation in brain function. In the context of Alzheimer's disease, these cells undergo a reactive transformation in response to amyloid-beta (A?) plaques, which are characteristic of the disease. In their attempt to eliminate these plaques, astrocytes inadvertently initiate a detrimental cycle. Initial research indicates that they engage in autophagy to absorb plaques and subsequently degrade them through the urea cycle. However, this breakdown process leads to an overproduction of GABA, which suppresses neuronal activity and results in memory deficits. Furthermore, this metabolic pathway produces hydrogen peroxide (H2O2), a toxic byproduct that exacerbates neuronal death and neurodegeneration.

The IBS research team aimed to identify the enzymes responsible for the excessive GABA production, seeking a method to inhibit its detrimental effects without disrupting other crucial brain functions. Through a combination of molecular analysis, microscopic imaging, and electrophysiological techniques, the researchers pinpointed SIRT2 and ALDH1A1 as key enzymes involved in the GABA overproduction observed in astrocytes affected by Alzheimer's.

Elevated levels of the SIRT2 protein were noted in the astrocytes of a commonly used Alzheimer's mouse model as well as in the brain tissues of deceased individuals diagnosed with the disease. When the expression of SIRT2 was inhibited in AD mouse models, researchers observed a partial restoration of memory capabilities and a decrease in GABA production. However, this effect was limited to short-term working memory, leaving spatial memory unaffected, raising further questions regarding the enzyme's role.

SIRT2 is implicated in the final stages of GABA synthesis, while the production of H2O2 occurs earlier in the metabolic process. Thus, it is likely that H2O2 continues to be generated regardless of SIRT2 activity. The findings indicated that blocking SIRT2 did not halt the production of H2O2, suggesting that neuronal degeneration could persist even with reduced GABA levels.

By identifying SIRT2 and ALDH1A1 as downstream targets, this research opens up possibilities for selectively inhibiting GABA production without influencing H2O2 levels. This distinction is crucial as it allows for a more nuanced investigation into the individual contributions of GABA and H2O2 to neurodegeneration.

The research team highlighted the significance of their findings, noting the limitations of current MAOB inhibitors, which inhibit both GABA and H2O2 production. By targeting enzymes such as SIRT2 and ALDH1A1, researchers can potentially focus on GABA inhibition while maintaining H2O2 levels, enabling the exploration of the distinct roles these components play in the progression of Alzheimer's disease.

While SIRT2 may not serve as a direct target for drug development due to its limited influence on neurodegeneration, this study lays the groundwork for more refined therapeutic approaches aimed at managing astrocytic reactivity in Alzheimer's disease.