Brain Star Award winners Iason Keramidis and Brendan McAllister

Brendan McAllister

Brendan McAllister

Iason Keramidis

Iason Keramidis

Dr. Iason Keramidis

CERVO Brain Research Centre, Université Laval

Dr. Brendan McAllister

Canadian Centre for Behavioural Neuroscience, University of Lethbridge

Scientific publication

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, Marie-Eve Paquet, Antoine G Godin, Majid H Mohajerani, Yves De Koninck (2023). Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer’s disease mutation. Brain, Volume 146, Issue 12, December 2023, Pages 4903–4915.

*co-first authors

A protein called KCC2 plays a crucial role in Alzheimer’s disease progression that could be targeted by new therapeutic approaches.

One of the changes seen in the early stages of Alzheimer’s disease is a loss of inhibitory brain signals. This is thought to disrupt normal signaling in neural networks by increasing excitability leading to cognitive defects. However, the mechanisms through which this occurred were unknown. A new study by Iason Keramidis and Brendan McAllister and colleagues shows that, in mouse lines carrying Alzheimer’s disease-related mutations, loss of a protein called KCC2, responsible for maintaining the robustness of inhibitory signals, occurs pre-symptomatically in important brain regions and plays a crucial role in disease progression.

The researchers first showed that loss of KCC2 occurred in two brain regions, the hippocampus and the prefrontal cortex, before the onset of Alzheimer’s disease related symptoms. They then showed that a drug called CLP290 could be used as a long-term treatment to prevent the decrease in KCC2, and this treatment protected against deterioration of learning and neural hyperactivity in the brain. In addition, restoring KCC2 by short term CLP290 treatment, after the start of the disease, effectively reversed spatial memory deficits and social behaviour impairments, further linking KCC2 function with Alzheimer’s disease-related cognitive decline.

This manuscript unveils an unexpected mechanism underlying the cognitive decline associated with Alzheimer’s disease. It represents a fundamental breakthrough since it points to a novel target falling outside of conventional avenues. Recent observations suggest that neuronal hyperactivity in key brain regions in early stages of Alzheimer’s disease results from disruption in inhibitory signalling. These observations prompted various attempts to restore inhibition to prevent or decelerate the disease progression, without success.

The new finding by Iason Keramidis and Brendan McAllister and colleagues highlights the important role of the KCC2 protein in disease progression, which had been overlooked in previous studies and explains why previous attempts were unsuccessful in restoring inhibition.

In addition, this study identifies a target with particularly good prospects for therapeutics since KCC2 is specific to the central nervous system (including the brain) and cannot be overstimulated. Lastly it emphasizes the critical importance of considering neural circuit-level interventions. This holistic approach represents a crucial stride towards innovative and impactful treatments for Alzheimer’s disease and other related neurodegenerative disorders.

About Iason Keramidis and Brendan McAllister

Dr. Iason Keramidis performed this research as a PhD student in the laboratory of Yves De Koninck at the CERVO Brain research centre, affiliated with Université Laval. Dr. Brendan McAllister worked as a post-doctoral researcher in the laboratories of Majid Mohajerani and Robert Sutherland at the University of Lethbridge’s Canadian Centre for Behavioural Neuroscience. As co-first authors of the publication, Iason Keramidis and Brendan McAllister performed most of the experiments and data analysis and contributed significantly to the writing and editing of the manuscript.

Dr. Keramidis received his PhD in January 2023 and is currently a post-doctoral researcher at Stanford University working with a world leader in the fields of optical imaging technology and neural circuits, Dr. Mark Schnitzer.

Dr. McAllister is currently a postdoctoral associate at the University of Calgary, working with Dr. Tuan Trang to study the role of immune cells in chronic pain and the response to opioid medications.

Sources of funding

Funding for this research was provided by: the Weston Brain Institute, the Canadian Institutes of Health Research (CIHR), the Canada Research Chair program, the Fonds de recherche du Québec—Santé (FRQS), Sentinel North (Canada First Research Excellence Fund), the Natural Sciences and Engineering Research Council of Canada (NSERC), Université Laval, the Fondation de la famille Lemaire.