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Contact Information

Richard Bergeron, MD, PhD, FRCPC

Research Activities

Work performed in the laboratory that is relevant to Alzheimer Disease Scientific Synopsis:
The Challenge: Alzheimer’s (AD) is an incurable disease characterized by the slow and progressive loss of neurons in the cortex and hippocampus, leading to dementia and eventually death. Plaques of aggregated beta-amyloid protein (Aβ) and neurofibrillary tangles of hyperphosphorylated tau protein are pathological hallmarks of the disease. While a small percentage of AD cases are hereditary and linked to dominant mutations in the Aβ biosynthesis pathway, the vast majority of cases are sporadic with heterogeneous causes, composed of both genetic and non-genetic risk factors. Despite this complexity, the dominant theory in AD research has been the Aβ cascade hypothesis, which proposes that aggregation of Aβ oligomers into plaques leads to cellular dysfunction and ultimately neuronal death. Yet, recent clinical trials targeting Aβ clearance have failed, suggesting that a broader, all-encompassing theory of AD based on new animal models and alternative therapies are desperately needed. In conjunction with the Aβ cascade hypothesis, an alternative hypothesis, based on research showing that changes in neuronal calcium (Ca2+) signaling precede histopathological markers and cognitive deficits in AD, has emerged. This hypothesis, which proposes that Ca2+ dyshomeostasis is an underlying cause of AD, suggests that animal models and therapies should be aimed at re-establishing Ca2+ homeostasis, rather than targeting Aβ deposits, which may be a consequence, rather than a cause of AD.
Innovative Approach: Dr. Bergeron’s laboratory has a long-standing interest in the sigma-1 receptor (Sig-1R), which regulates Ca2+ homeostasis. This receptor has roles in neuroprotection, neurite outgrowth and cognition. Recently, they reported that Sig-1R activation increases NMDA receptors at the cell surface, a key receptor in synaptic plasticity and cognition. Intriguingly, the Sig-1R has been implicated in AD disease in a variety of ways. First, Sig-1R binding sites are decreased in patients suffering from AD. Second, a polymorphism in the Sig-1R gene, which reduces Sig-1R expression, is a risk factor for AD. Third, a major drug used in AD treatment, donepezil, targets Sig-1R. Finally, and most significantly, Sig-1R agonists are neuroprotective and anti-amnesic in AD mouse models and protect against Aβ toxicity in vitro. Taken together, this suggests that an animal model based on loss of Sig-1Rs could provide an all-encompassing model of AD where drugs targeting Ca2+ homeostasis could be tested. The scientific team of Dr. Bergeron is working hard to investigate how Sig-1R could become a therapeutic target for the prevention of this terrible disease.

Alzheimer Disease Lay Summary:
There are currently over 500,000 Canadians suffering from Alzheimer’s disease or another form of dementia, and the number is steadily increasing every day. By the year 2050 an estimated 1.5 million people in Canada, and an additional 150 million people worldwide, will suffer from Alzheimer’s disease. Surprisingly, 2/3 of all Alzheimer patients are women, suggesting that the drop of steroid hormone may play in role in the pathophysiology of the disease. Moreover, these estimates do not include the countless silent sufferers dealing with the social, emotional and financial turmoil associated with caring for loved ones stricken by this disease. Alzheimer’s disease progresses slowly, first robbing sufferers of their short-term memories, like where they left their keys, then wiping their long-term memories from their brains, like the names of their loved ones, and finally taking away their ability to do simple daily tasks, like taking a shower. There is currently no cure for Alzheimer’s disease. Promising therapies targeted at amyloid beta, a distinguishing feature of the disease, failed to improve patient outcomes in recently completed clinical trials. Therefore, there is an urgent need for new hypotheses and therapeutic strategies aimed at other key features of the disease, such as early changes in calcium signaling that precede cognitive decline and taking into account the potential differential effects of amyloid beta in females compared to males. Here, we propose to create and test a novel mouse model based on the Sigma-1 Receptor, a calcium-regulating molecule that, when activated, improves many of the features of Alzheimer’s disease in mouse models. By creating this new mouse model we hope to open the door towards new theories and new treatments based on a better understanding of the underlying causes of Alzheimer’s disease.

Work performed in the laboratory that is relevant to Ischemic Stroke Scientific Synopsis:
The Challenge: For many years, it has been suggested that cell death induced by ischemic stroke is the result of glutamate accumulation in the extracellular space and over-activation of the ionotropic NMDA receptors. This allows excessive influx of intracellular Ca2+ and leads to neurotoxicity. In the last few decades, Pharmaceutical Companies have designed drugs that could act as antagonists at NMDA receptors. However, large-scale multicenter clinical trials using NMDA receptor antagonists have failed to demonstrate satisfactory neuroprotective effects. In contrast to glutamate, the role of glycine in ischemia is far less understood. Glycine plays three major roles in neurotransmission in the central nervous system. First: Glycine has an inhibitory function that is mediated by ionotropic glycine receptors (GlyRs). While synaptic GlyRs are ubiquitous throughout the spinal cord, there is an increasing body of evidence to suggest that GlyRs are expressed mainly at extrasynaptic sites in the hippocampus. Second: Low concentration (μM) of glycine modulates glutamatergic excitatory neurotransmission by acting as a co-agonist at NMDARs. Third: High concentrations (mM) of glycine have been reported to prime NMDA receptors for internalization in vitro but no evidence that such high doses of glycine could occur in vivo. The in vitro data generated by my lab suggest that a high levels of glycine result in a rapid, dynamin-dependent internalization of synaptic NMDA receptors. This may be a mechanism to reduce NMDA receptor overactivation during ischemic events. If this is the case, then increasing of extracellular glycine concentrations should reduce stroke volume following an ischemic insult in vivo.

Innovative Approach: we found that a high concentration (1 mM) of glycine induced internalization of NMDA receptors in vitro. Using either an in vitro model of ischemia (oxygen glucose deprivation: OGD) or an in vivo model of ischemia (photothrombosis: PT), we found that mice that have a high level of ambient glycine, the toxic effect of OGD or PT is significantly attenuated as determined by a reduction stroke volume and cell death. Dr. Bergeron hypothesizes that this internalization is dependent of the glycine modulatory site (GMS) occupancy and is mediated preferentially via GluN2A-containing NMDARs. This hypothesis is currently being testing using animals with high or low concentration of glycine in the brain.

Ischemic Stroke Lay Summary:
Our brain works similar to an automobile: to function it requires a continuous supply of energy. Instead of using gasoline our brain uses glucose and oxygen. Both are carried to the brain by our blood. When a large energy demand of the brain is not completely satisfied due to a decreased or completely interrupted flow of blood, a pathological condition known as brain ischemia or stroke occurs. A few minutes after a stroke, a "serial killer" emerges from the cells of the brain, neurons. This "serial killer" is called glutamate and it induces excitation of most neurons of the brain. The brain needs some level of excitation to maintain communication amongst the neurons, however too much excitation can cause death or permanent damage to the brain. Stroke can occur at any time and this medical condition can affect any of us. Currently there is no medication that can halt the "serial killer" and that is the reason why stroke is a real challenge for neuroscientists. The objective of the research of Dr. Bergeron is to uncover the potential important role of a small molecule that is found in huge quantities in the brain, this molecule is called glycine. Preliminary results suggest that we can make use of glycine to protect the brain when stroke occurs. For several decades, glycine was known by neuroscientists to play an important role in the spinal cord by providing some inhibition (i.e. to slow down the electrical activity when there is too much excitation). However, preliminary data suggests a similar role for glycine in cortical regions of the brain where stroke could occur. The merit of this research program of Dr. Bergeron is its ability to integrate highly sophisticated and innovative techniques in order to address a crucial question: how can glycine protect the brain and stop the "serial killer" when an ischemic condition occurs? The ultimate goal is to bring the scientific community one step closer to finding a much-needed cure for stroke.

Members of the Laboratory of Dr. Bergeron include graduate students, postdoctoral fellows, research associates and lab technicians.
As of July 2016:

Graduate Students:
Madelaine Abraham, Nina Ahlskog, Pamela Khacho, MaryLine Lalande, Louis-Alexandre Tasse, Jack Wang.

Postdoctoral Fellows: Prakash Chudalayandi, Melissa Snyder.

Research Associate: Adrian Wong.

Lab Technicians: Elitza Hristrova, Kieran McCann, Alexandra Sokolovski.

Administrative Assistants: Denise Joanisse, Kelsey Oldland.    Research Administrative Assistant: Nella Bianconi