Previous studies have actually revealed that even before Alzheimers symptoms appear, brain activity is interrupted in individuals who go on to develop the illness. This offered us the idea of taking a look at the role of KCC2 in an animal design of Alzheimers disease,” adds the researcher.
To do this, researchers utilized mouse lines expressing a symptom of Alzheimers illness. These two areas are also affected in people suffering from Alzheimers illness.
” Our results do not imply that the loss of KCC2 causes Alzheimers illness,” firmly insists Prof. De Koninck.
Researchers discovered that bring back KCC2, a neuron-regulating mechanism minimized in Alzheimers illness, can possibly reverse some of the diseases cognitive manifestations in mice. The particle utilized for this, CLP290, revealed positive outcomes in mice but isnt ideal for human usage, prompting the look for other KCC2-activating particles.
Scientists from Laval University and the University of Lethbridge have effectively reversed particular cognitive manifestations connected to Alzheimers disease in an animal design. Their findings were just recently published in the journal Brain.
” Although this has yet to be demonstrated in human beings, we believe that the mechanism we have revealed makes up a really intriguing healing target, since it not just slows down the progression of the illness but likewise partly restores specific cognitive functions,” comments study leader Yves De Koninck, a professor in the Faculty of Medicine and scientist at Laval Universitys CERVO research study.
Previous research studies have actually revealed that even before Alzheimers signs appear, brain activity is interrupted in people who go on to establish the illness. “There is neuronal hyperactivity and signal poor organization in the brain. Our hypothesis is that a mechanism that manages neuronal activity, more specifically the one responsible for inhibiting neuronal signals, is disrupted,” explains the scientist.
The main inhibitor of neuronal signals in the human brain is the neurotransmitter GABA. It works in close partnership with a cotransporter, KCC2.
” A loss of KCC2 in the cell membrane can cause neuronal hyperactivity. One research study has actually already revealed that KCC2 levels were decreased in the brains of departed Alzheimers patients. This provided us the concept of examining the role of KCC2 in an animal model of Alzheimers disease,” includes the scientist.
Promising Results in Mice
To do this, researchers utilized mouse lines expressing a manifestation of Alzheimers illness. The researchers discovered that when these mice reached the age of 4 months, KCC2 levels decreased in 2 areas of their brains: the hippocampus and the prefrontal cortex. These two areas are also impacted in people experiencing Alzheimers disease.
In light of these outcomes, the researchers turned to a particle developed in their lab, CLP290, a KCC2 activator that prevents its depletion. In the brief term, the administration of this molecule to mice that already had actually decreased KCC2 levels improved their spatial memory and social habits. In the long term, CLP290 secured them versus cognitive decrease and neuronal hyperactivity.
” Our results do not imply that the loss of KCC2 causes Alzheimers disease,” firmly insists Prof. De Koninck. “On the other hand, it does appear to cause an ionic imbalance causing neuronal hyperactivity that can result in neuronal death. This recommends that by preventing the loss of KCC2, we might slow down and perhaps even reverse specific manifestations of the disease.”
For different factors, CLP290 can not be used in human beings. Professor De Konincks team is looking for other KCC2-activating molecules that would be well endured by Alzheimers sufferers.
” We have developed new particles which are currently being assessed in our laboratory. In parallel with this research study, we are evaluating drugs that are utilized for functions aside from Alzheimers in humans, in order to evaluate their effects on KCC2. Rearranging an existing drug would speed up work on this brand-new healing avenue,” stresses the researcher.
Recommendation: “Restoring neuronal chloride extrusion reverses cognitive decrease linked to Alzheimers illness anomalies” 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, 8 August 2023, Brain.DOI: 10.1093/ brain/awad250.
The other signatories of the research study 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 Laval University, and Brendan McAllister, Edris Rezaei, Phil Degagne, Mojtaba Nazari, Samsoon Inayat, and Majid Mohajerani, from the University of Lethbridge.
