2023-08-14 04:00:05
A team of researchers announces, in the journal Brain, that they have succeeded in reversing certain cognitive manifestations associated with Alzheimer’s in an animal model of the disease. “Even if the demonstration remains to be done in humans, we believe that the mechanism that we have highlighted (Light is all the electromagnetic waves visible by the eye…) constitutes a therapeutic target (Therapeutic (from the Greek therapeuein, to cure) is the part of medicine that…) very interesting because it is not limited to slowing down the progression of the disease (The disease is an alteration of the functions or the health of a living organism, animal, etc.), but that it partially restores certain cognitive functions”, comments the head of the study, Yves De Koninckprofessor at the Faculty of Medicine (Medicine (from the Latin medicus, “that heals”) is science and…) and researcher (A researcher (fem. researcher) designates a person whose job is to do …) at the Research Center (Scientific research designates in the first place all the actions undertaken with a view to…) CERVO of Laval University (Laval University is one of the largest universities in Canada. She has like…).
When there is a decrease in the KCC2 molecule in the cell membrane of neurons, their ionic balance is disturbed and they become hyperactive, as this illustration suggests. This hyperactivity can lead to the death of neurons.
Getty Images/Koto Feja
Previous studies have shown that even before Alzheimer’s symptoms appear, brain activity is disrupted in people who will develop the disease. “There is neuronal hyperactivity and a disorganization of signals in the brain, explains the researcher. Our hypothesis is that a mechanism that regulates the activity neuron, specifically the one responsible for inhibiting neural signals, is disrupted.”
The main inhibitor of neural signals in the human brain is the neurotransmitter GABA. It works in close collaboration with a cotransporter, KCC2. It is an ion pump, located in the cell membrane, which circulates chloride ions and potassium ions (Potassium is a chemical element, symbol K (Latin: kalium, de…) between the inside and outside of neurons, says Professor De Koninck.
The GABA receptor (in blue) allows negative chloride ions (in yellow) to enter neurons, which inhibits the transmission of nerve impulses. For this inhibition to be maintained, chloride ions must be constantly expelled from the cell. The KCC2 cotransporter (in green) performs this task by pumping out a negative chloride ion along with a positive potassium ion (in pale green).
Bruce Blauss/Sylvain Côté
“When there is a loss of KCC2 in the cell membrane, the level of chloride ions increases inside neurons, and GABA-mediated inhibition is disrupted, he continues. This can lead to hyperactivity One study has already shown that levels of KCC2 were reduced in the brains of deceased people who had suffered from Alzheimer’s, which gave us the idea to examine the role of KCC2 in an animal model of Alzheimer’s disease.”
To do this, the researchers used a line of mice that express one of the two main manifestations of Alzheimer’s in humans: the formation of amyloid plaques in the brain. As expected, these plaques appeared in the brains of these mice and their abundance increased with age.
The researchers found that when these mice reached 4 months of age, KCC2 levels decreased in two regions of their brains. These two regions, the hippocampus and the prefrontal cortex, are also affected in people with Alzheimer’s. “The greater the loss of KCC2, the more amyloid plaques the mice had,” notes Professor De Koninck.
In light of these results, the researchers used a molecule developed in their laboratory, CLP290, an activator of KCC2 which prevents its reduction. In the short term, the administration of this molecule to mice which already had reduced levels of KCC2 led to an improvement in their spatial memory and their social behaviors. In the long term, CLP290 protected them against a decrease in cognitive abilities and against neuronal hyperactivity.
“Our results do not imply that the loss of KCC2 causes Alzheimer’s, insists Professor De Koninck. preventing the loss of KCC2 could slow down and possibly even reverse some manifestations of the disease.”
For various reasons, CLP290 cannot be used in humans. Professor De Koninck’s team is looking for other KCC2 activating molecules that would be well tolerated by people suffering from Alzheimer’s. “We have developed new molecules that are currently being evaluated in our laboratory. Alongside this research, we are testing drugs that are used for purposes other than Alzheimer’s in humans in order to assess their effects on KCC2. The repositioning of an existing drug would accelerate work on this new therapeutic avenue”, underlines the researcher.
The other signatories of thestudy published in Brain are Iason Keramidis, Julien Bourbonnais, Feng Wang, Dominique Isabel, Marie-Eve Paquet, Romain Sansonetti, Annie Barbeau, Lionel Froux and Antoine Godin, from the University (A university is an institution of higher education whose objective is the…) Laval, and Brendan McAllister, Edris Rezaei, Phil Degagne, Mojtaba Nazari, Samsoon Inayat and Majid Mohajerani, from the University of Lethbridge (The University of Lethbridge is located in the city of Lethbridge, on the west bank of…).
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