Researchers have identified that reactivating KCC2, a neuronal regulatory mechanism that is diminished in Alzheimer’s disease, could potentially alleviate some of the cognitive symptoms in mouse models. Although the chemical compound CLP290 demonstrated promise in mice, it is unsuitable for human application, necessitating the quest for alternative molecules that activate KCC2.
Scholars from Laval University and the University of Lethbridge have been successful in mitigating specific cognitive impairments related to Alzheimer’s disease in animal subjects. The results of their research were recently published in the academic journal Brain.
Yves De Koninck, the principal investigator and a faculty member at Laval University’s Faculty of Medicine as well as a researcher at the CERVO research center, remarked, “Although these findings have not been replicated in humans, we are optimistic that the mechanism we have identified serves as a compelling therapeutic target. It offers the dual benefit of not just slowing disease progression but also partially reinstating certain cognitive abilities.”
Earlier investigations have revealed that individuals who eventually develop Alzheimer’s disease exhibit disruptions in brain activity even before the onset of recognizable symptoms. “Neuronal hyperactivity and disorganized signaling within the brain are evident. We posit that the mechanism regulating neuronal activity, specifically the one that inhibits neuronal signaling, is compromised,” elucidates the lead researcher.
GABA, a neurotransmitter, acts as the primary inhibitor of neuronal signaling in the human brain. It operates in conjunction with a cotransporter named KCC2, an ion pump situated in the cell membrane responsible for the movement of chloride and potassium ions in and out of neurons,” recalls Professor De Koninck. Stabilizing this ion pump may decelerate or even reverse the pathological developments.
“The deficiency of KCC2 in the cellular membrane can result in neuronal hyperactivity. One previous study revealed that the brains of deceased Alzheimer’s patients had diminished levels of KCC2. This led us to probe the role of KCC2 in animal models of Alzheimer’s disease,” adds the researcher.
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Encouraging Outcomes in Rodent Models
To carry out their study, the research team employed mouse strains that displayed Alzheimer’s-like symptoms. They discovered that by the age of four months, these mice experienced a reduction in KCC2 levels in two key brain regions: the hippocampus and the prefrontal cortex. Both of these regions are similarly affected in human Alzheimer’s patients.
In response to these observations, the researchers utilized a laboratory-developed molecule, CLP290, to activate KCC2 and inhibit its depletion. Short-term administration of this molecule to mice with already reduced KCC2 levels showed improvements in spatial memory and social interaction. Over an extended period, CLP290 provided protection against cognitive deterioration and neuronal overactivity.
“While our data do not imply that KCC2 deficiency is the root cause of Alzheimer’s disease, it seems to induce an ionic imbalance, leading to neuronal hyperactivity that may result in neuronal death. Therefore, preventing the depletion of KCC2 may slow down and even reverse certain aspects of the disease,” asserts Professor De Koninck.
Unfortunately, CLP290 is not a viable treatment option for humans. The research team led by Professor De Koninck is now in pursuit of alternative KCC2-activating molecules that would be safe for human application.
“We are currently assessing new compounds in our laboratory. Simultaneously, we are examining drugs with different primary applications to gauge their effects on KCC2. Repurposing an existing pharmaceutical could expedite research into this novel treatment approach,” highlights the lead researcher.
Citation Information
The study, titled “Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer’s disease mutations,” was authored by Iason Keramidis, Brendan B McAllister, Julien Bourbonnais, Feng Wang, Dominique Isabel, Edris Rezaei, Romain Sansonetti, Phil Degagne, Justin P Hamel, Mojtaba Nazari, Samsoon Inayat, Jordan C Dudley, Annie Barbeau, Lionel Froux, Antoine G Godin, Majid H Mohajerani, and Yves De Koninck. It was published on August 8, 2023, in Brain. DOI: 10.1093/brain/awad250
Contributors to the study published in Brain include Iason Keramidis, Julien Bourbonnais, Feng Wang, Dominique Isabel, Marie-Eve Paquet, Romain Sansonetti, Annie Barbeau, Lionel Froux, and Antoine Godin from Laval University, as well as Brendan McAllister, Edris Rezaei, Phil Degagne, Mojtaba Nazari, Samsoon Inayat, and Majid Mohajerani from the University of Lethbridge.
Frequently Asked Questions (FAQs) about Alzheimer’s Therapeutic Target
What is the main discovery of the research conducted by Laval University and the University of Lethbridge?
The primary discovery is the identification of KCC2, a neuron-regulating mechanism, as a potential therapeutic target for Alzheimer’s disease. By reactivating this mechanism in mice, researchers were able to alleviate some cognitive symptoms associated with the disease.
Who led the study and where was it published?
The study was led by Yves De Koninck, a professor at Laval University’s Faculty of Medicine and a researcher at the CERVO research center. The findings were published in the academic journal Brain.
What molecule did the researchers use in the study?
The researchers used a molecule named CLP290, which is a KCC2 activator, in mouse models exhibiting Alzheimer’s-like symptoms.
Can CLP290 be used for human treatment?
No, CLP290 is not suitable for human application. The research team is actively searching for alternative KCC2-activating molecules that would be well-tolerated by humans.
What are the implications of the study for Alzheimer’s treatment?
The study suggests that KCC2 could serve as a compelling therapeutic target. By reactivating or stabilizing this mechanism, it may be possible to not only slow down the progression of Alzheimer’s but also partially restore certain cognitive functions.
Did the study prove that a lack of KCC2 causes Alzheimer’s disease?
No, the study does not claim that a lack of KCC2 is the root cause of Alzheimer’s disease. It suggests that a deficiency in KCC2 can lead to an ionic imbalance and neuronal hyperactivity, which may contribute to the disease’s pathology.
What regions of the brain were primarily affected in the mouse models?
In the mouse models used for the study, KCC2 levels were found to be decreased in the hippocampus and the prefrontal cortex, both of which are regions also affected in humans with Alzheimer’s disease.
Are there any human trials planned based on these findings?
The text does not specify plans for human trials. However, the research team is investigating other KCC2-activating molecules and drugs for possible human application.
What is the significance of the neurotransmitter GABA in this study?
GABA acts as the primary inhibitor of neuronal signaling in the human brain and works in collaboration with KCC2. Maintaining or reactivating this mechanism could have therapeutic benefits for Alzheimer’s patients.
Are there existing drugs that could potentially affect KCC2?
The research team is currently evaluating drugs with different primary applications to assess their effects on KCC2. Repurposing an existing pharmaceutical could accelerate the development of this new therapeutic approach.
More about Alzheimer’s Therapeutic Target
- Original Study in Brain Journal
- Laval University Faculty of Medicine
- University of Lethbridge Research
- CERVO Research Center
- Alzheimer’s Disease Overview
- Role of GABA in the Brain
- Neurotransmitter Mechanisms
9 comments
the hippocampus and prefrontal cortex, huh? I’ve read those are crucial for memory and decision-making. makes sense they’d focus on those areas.
wow! If this KCC2 thing works as well as it does in mice, big pharma’s gonna be all over this. Hope it actually leads to somethin good and not just profits.
Yves De Koninck is a big name in this field. If he’s on it, there’s definitely some weight behind these findings. keen to see where this research goes next.
interesting that they’re looking at existing drugs too. Could speed things up big time, especially if they find something that works.
Awaiting the human trials. If this pans out, it’s more than just a leap in Alzheimer’s treatment, it’s a jump for neuroscience in general.
So they’re saying CLP290 isn’t suitable for humans, right? What’s the deal there, and why did they even bother with it in the first place?
I’m no scientist but this sounds promising. Hope it works out and they can make it work for humans too. Would be a miracle for so many suffering families.
Seriously impressive work here. It’s hard to overstate just how big a deal this could be. A way to not only halt but even reverse some Alzheimer’s symptoms? count me in.
Wow, this is a game changer, isnt it? If they can take this from mice to humans, we’re looking at a major shift in how we handle Alzheimer’s.