New Alzheimer’s Research Identifies Key Enzyme Behind Memory Loss
October 26, 2024
A groundbreaking study from the Institute for Basic Science (IBS) has pinpointed a previously unknown enzyme, SIRT2, as a major contributor to the memory loss associated with Alzheimer’s disease (AD). This revelation, spearheaded by Director C. Justin Lee at the IBS Center for Cognition and Sociality, shines a light on the role of astrocytes in cognitive decline, specifically their tendency to overproduce the inhibitory neurotransmitter GABA.
For years, astrocytes were considered mere support cells for neurons. However, research now reveals they actively participate in brain function. In Alzheimer’s, astrocytes become “reactive” in response to amyloid-beta (Aβ) plaques, protein clumps characteristic of the disease. While these reactive astrocytes attempt to clear the plaques, this process inadvertently triggers a cascade of harmful events. They begin by engulfing the plaques through autophagy (Kim and Chun, 2024) and then attempt to break them down using the urea cycle (Ju et al, 2022), processes identified in prior studies. Unfortunately, this breakdown leads to an excessive production of GABA, which dampens neuronal activity, impairing memory. Additionally,the process generates hydrogen peroxide (H2O2),a highly toxic byproduct that exacerbates neuronal death and neurodegeneration.
This new research offers hope for more targeted Alzheimer’s treatments. Imagine current Alzheimer’s drugs like a broad-spectrum antibiotic, while this new understanding of SIRT2 allows researchers to develop treatments acting like a precision guided missile targeting specifically the damaging effects of GABA overproduction.
Unlocking the GABA Puzzle: SIRT2’s Role
The IBS research team embarked on a mission to identify the specific enzymes responsible for this excessive GABA production. Their goal was to find a way to selectively block its detrimental effects without disrupting other vital brain functions. Through meticulous molecular analysis, advanced microscopic imaging, and electrophysiological studies, the researchers identified SIRT2 and ALDH1A1 as key enzymes involved in the overproduction of GABA in astrocytes affected by Alzheimer’s.
Mridula BHALLA, the lead author of the study and a post-doctoral researcher at IBS, noted the important findings: “When we inhibited the astrocytic expression of SIRT2 in AD mice, we observed partial recovery of memory and reduced GABA production.” This suggests that targeting SIRT2 could offer a potential therapeutic avenue for alleviating memory loss in Alzheimer’s patients.
However, the research also revealed a more complex picture. “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,” said BHALLA.This highlights the nuanced role of SIRT2 and the need for further investigation.
The H₂O₂ Connection: A Critical Consideration
The study further revealed that SIRT2 participates in the final stage of GABA production, while H2O2 is generated earlier in the process.This temporal difference has significant implications. As Director C. Justin LEE explained, “Indeed, we found that inhibition of SIRT2 continued H2O2 production, indicating that neuronal degeneration might continue even though GABA production is reduced.” This highlights a critical challenge: simply blocking SIRT2 might reduce GABA levels but fail to address the ongoing damage caused by H2O2.
This finding underscores the complexity of Alzheimer’s disease and the need for multi-pronged therapeutic approaches. A treatment solely targeting SIRT2 might offer only partial relief, whereas a combined strategy that addresses both GABA and H2O2 could prove more effective. this is analogous to treating heart disease, where doctors often prescribe medications to lower cholesterol *and* manage blood pressure for optimal outcomes.
Implications and Future Directions
The identification of SIRT2 and ALDH1A1 as downstream targets allows scientists to selectively inhibit GABA production without impacting H2O2 levels. This is a major step forward, enabling researchers to isolate the effects of GABA and H2O2 and study their individual contributions to neurodegeneration in more detail.
Director C. Justin LEE emphasized the significance of this breakthrough: “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 itself may not be an ideal direct drug target due to its limited impact on neurodegeneration, this research opens the door for the growth of more precise therapeutic strategies aimed at controlling astrocytic reactivity in Alzheimer’s disease. This could lead to novel treatments that specifically target the harmful effects of GABA while also addressing the damaging effects of H2O2, perhaps offering more thorough relief for Alzheimer’s patients. For example, future research will likely focus on developing drugs that can simultaneously inhibit SIRT2 *and* neutralize H2O2. Another promising avenue is exploring gene therapy to reduce the expression of SIRT2 in astrocytes.
Alzheimer’s Disease: A Snapshot
Alzheimer’s disease is a devastating neurodegenerative disorder affecting millions of americans. Understanding the underlying mechanisms driving the disease is crucial for developing effective treatments. This table summarizes key aspects of Alzheimer’s disease.
| Aspect | Description |
|---|---|
| Hallmarks | Amyloid-beta plaques and neurofibrillary tangles |
| Key Players | Neurons, astrocytes, microglia |
| Symptoms | Memory loss, cognitive decline, behavioral changes |
| current Treatments | Focus on symptom management, no cure available |
| Prevalence (U.S.) | Millions affected, numbers rising with aging population |
Recent developments in Alzheimer’s Research
While this study focuses on SIRT2, other areas of Alzheimer’s research are also showing promise.Clinical trials are underway for drugs that target amyloid plaques and neurofibrillary tangles. lifestyle interventions, such as diet and exercise, are also being investigated for their potential to slow cognitive decline. The FDA’s recent approval of certain anti-amyloid drugs has sparked debate within the medical community, but underscores the urgency and dedication to finding effective treatments.
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Alzheimer’s Breakthrough: Interview with Director C. Justin Lee on SIRT2 and Memory Loss
October 27, 2024
Archyde News is thrilled to bring you an exclusive interview with Director C. Justin Lee, from the Institute for basic Science (IBS), about a groundbreaking study on Alzheimer’s disease. Director Lee, your team has made an exciting discovery linking the enzyme SIRT2 to memory loss in Alzheimer’s. Could you start by giving us an overview of your findings?
The SIRT2 Discovery: Unraveling the Alzheimer’s Puzzle
Director Lee: Certainly. Our research has identified SIRT2 as a key player in the excessive GABA production by astrocytes in the brains of Alzheimer’s patients. Thes astrocytes, the support cells of the brain, become overactive in response to amyloid-beta plaques. This overactivity leads to elevated GABA levels, which then inhibits neuronal activity, causing memory impairment. Inhibiting SIRT2 could potentially alleviate this specific problem, but it proved to be more complex than we thought.
Archyde News: The study also highlighted a connection with hydrogen peroxide (H₂O₂). How does this factor into the complexity, and what are the therapeutic implications?
Director lee: That is a crucial point. We found that SIRT2 is involved in a later stage of the GABA production process, after H₂O₂ is generated. This means that even if we block SIRT2 and reduce GABA, H₂O₂ production might continue, potentially leading to ongoing neuronal damage. This highlights the need for multi-targeted treatments, possibly including both GABA inhibitors and H₂O₂ scavengers. We aim to target both issues.
Focusing on Astrocytes as Targets in Alzheimer’s Treatments
Archyde News: The study specifically notes the important functions of astrocytes.What made you look into them in the first place? And how do you think this new understanding of astrocytes change therapeutic strategies?
Director Lee: For a long time, astrocytes were viewed as simply supportive. We now know they’re active participants in brain function, and their reactivity plays a major role in the disease. They respond directly to amyloid plaques,triggering GABA overproduction.By targeting their reactivity, we shift away from the broad-spectrum strategies used so far and allow for more targeted interventions. this opens up doors for more effective treatments.
Archyde News: The article mentions that inhibiting SIRT2 in mice showed only partial recovery of memory. What are your future directions in research following this observation?
Director Lee: Our team plans to investigate the effects of inhibiting the ALDH1A1 enzyme, which we also identified, to determine its effect on the damage of H₂O₂. we have to know more about the complete process.
The future Outlook: Multi-pronged approach
Archyde news: Alzheimer’s disease is a complex condition.What are the biggest challenges in the coming years in your view?
Director Lee: The biggest challenge is the complexity. Alzheimer’s isn’t just one thing; it’s a cascade of events. We must continue to identify the specific points in this cascade where we can intervene safely and effectively. This means focusing on the interplay of different aspects of the disease, such as amyloid plaques and neurofibrillary tangles, H₂O₂ levels, inflammation, and synaptic dysfunction. A multi-pronged approach, targeting several factors concurrently, is more likely to yield more effective treatments than focusing on only one factor.
Archyde News: This is captivating work, Director Lee. What do you hope the impact of your research will be on the future of Alzheimer’s treatment?
Director Lee: We hope our work will contribute to personalized medicine regarding Alzheimer’s disease. Ultimately, we aim to provide options for people to live meaningful lives, and to protect future generations. We’re also hoping that these findings will inspire more researchers to engage in this type of work.
Archyde News: This is an amazing finding that will encourage many people. Thank you for sharing your insights with us.
Reader’s Corner
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