UNews - Dr. Majid Mohajerani

U of L researchers use Alberta Prion Research Institute grant to help unlock molecular mechanisms involved in Alzheimer's disease

caroline.zentner — Thu, 08 Feb 2018 18:03:46 +0000

Drs. Athan Zovoilis, a professor of bioinformatics in the Department of Chemistry and Biochemistry, and Majid Mohajerani, a professor of neuroscience, have secured a grant worth $200,000 from the Alberta Prion Research Institute to study how the misfolding of proteins causes symptoms of Alzheimer’s disease.

Dr. Athan Zovoilis holds a MinION sequencer, a tiny device that runs off of a USB plug.

“We know that protein misfolding, a molecular process in which biomolecules called proteins get an abnormal 3D conformation, is associated with the development of this debilitating disease. However, we still don’t have a clear picture of how this protein misfolding leads to brain cell death and subsequently to dementia,” says Zovoilis, who was recruited to the U of L from Harvard Medical School as a Canada Research Chair in RNA Bioinformatics and Genomics. “Now we have new genomic technologies, such as next-generation sequencing, that give the ability to better understand what is happening at the molecular level in the brain cells due to protein misfolding.”

Zovoilis’ RNA Genomics Laboratory is the first in Western Canada to get access to a new cutting-edge sequencing platform called PromethION that enables a better insight into the biology of Alzheimer’s disease through a novel approach called direct, long range RNA-sequencing.

Identifying the mechanisms that underlie Alzheimer’s disease is a big challenge so Zovoilis teamed up with Mohajerani to approach the problem in an interdisciplinary manner. The team tackling the question consists of bioinformaticians, who use software tools to understand biological data, wet lab scientists and neuroscientists.

Dr. Majid Mohajerani

“Our research interests and experimental skill sets are complementary,” says Mohajerani. “We are searching for biomarkers at different levels, from molecules to brain network activity, that could be used for early diagnosis and disease progression. We have state-of-the-art research facilities within both the Department of Neuroscience and Chemistry & Biochemistry and capitalizing on complementary resources will help us reach consensus on our scientific voyage to understand the neurobiology of Alzheimer’s disease.”

Zovoilis and Mohajerani are using these new genomic technologies to examine the relationship between misfolded proteins and brain cell death more closely. They’ll be looking specifically at a group of biomolecules called non-coding RNAs they suspect may be involved in the process.

“At the moment, there’s really no cure for Alzheimer’s disease,” says Zovoilis. “In order to design drugs against specific targets within the cells, we first need to know the pathway from protein misfolding to cell death. That is what’s missing. We know the trigger — protein misfolding and the plaques — and we know the result — cell death — but we have no idea what happens in between. By identifying new pathways, we might be able to also identify potential targets for therapeutic intervention.”

The research work has begun and Zovoilis says they are already seeing very encouraging results. In the next two years, they plan to have published the research and set the foundations of followup projects to determine how intervening in the process might accelerate or delay the progress of the disease.

“There is a significant time window that separates basic science from the moment we have a new drug on the market,” says Zovoilis. “If we don’t start now, we cannot expect to have a new treatment 10 years from now. It was very wise of the province to create and support the Alberta Prion Research Institute, as well as support us to establish a frontline RNA Genomics Laboratory here at the U of L. This is a game changer and it is really going to help us face this challenge. “

Students benefit from training opportunities through U of L’s partnership with the ��Ѹ��Դ��߿�Ƭ of California Irvine

caroline.zentner — Thu, 14 Sep 2017 20:08:02 +0000

Dr. Bruce McNaughton, a neuroscientist and recipient of the 10-year Alberta Innovates Health Solutions Polaris Award in 2008, has been somewhat of a double agent for the past few years.

As the province’s only Polaris-award winner, he’s been teaching and conducting research at the Canadian Centre for Behavioural Neuroscience (CCBN) at the ��Ѹ��Դ��߿�Ƭ of Lethbridge. Then in 2014, McNaughton was jointly appointed a distinguished professor at the ��Ѹ��Դ��߿�Ƭ of California, Irvine (UCI) at their Center for the Neurobiology of Learning and Memory (CNLM).

“The idea here was that, by having a joint appointment at UCI, I could expand my research funding, my collaborations and my ability to train graduate students and post-doctoral fellows, as well as my research funding,” says McNaughton. “Since that time, we’ve had at least five visits by students and post-docs in California getting trained on our advanced imaging technology here, and I’ve had one technician and three trainees do rotations down there. These opportunities for CCBN trainees and faculty members will clearly enrich the U of L’s education and research efforts.”

Part of the Polaris mandate was to expand international collaborations and UCI was a good fit, based on McNaughton’s research interests in learning, memory and memory disorders associated with aging and brain diseases. A recent area of interest for McNaughton is something called cognitive reserve, which is one of the best predictors of healthy brain aging. This phenomenon describes a situation in which two brains may show the same level of pathology, such as plaques and tangles, yet the one that has had more education, leads an active and varied lifestyle, speaks multiple languages and engages in exercise will show fewer behavioural signs of dementia.

“We’re interested in understanding the neural circuit mechanisms that underlie cognitive reserve,” says McNaughton. “It’s a complicated question; it involves studying the dynamics of the interaction of brain cells, how efficiently they represent data and things of that nature.”

Thanks to the hiring of Dr. Majid Mohajerani, infrastructure support from the Polaris award and the Canada Foundation for Innovation (CFI), the CCBN is equipped with a two-photon optical imaging system that allows researchers to analyze how the brain codes and stores information by monitoring hundreds of individual neurons simultaneously while animals are behaving. This involves placing mice in a virtual reality setup where they run on a treadmill with their head fixed under the microscope.

“It’s like they’re running around in the world. The fact that they’re running causes the hippocampus — the part of the brain that is essential for creating new memories and retrieving them, at least initially — to update its pattern as though the animal were running in a real world,” says McNaughton.

Sandra Gattas looks to map cognitive reserve through neural activity

One of McNaughton’s students at UCI, Sandra Gattas, wants to know if cognitive reserve can be seen at the neural level. Gattas, a student in the MD/PhD program, is currently at the U of L implementing an experiment she designed to answer that question. She’s working with a mouse model and comparing differences in neural activity between a group of mice participating in environmental enrichment activities and a group receiving no enrichment. As her research progresses, she also intends to perform the same experiment with mice genetically designed to mimic Alzheimer’s disease.

Sandra Gattas, a UCI student in the MD/PhD program, has been researching cognitive reserve at the CCBN.

“I’m measuring brain activity with the two-photon microscope as I gradually increase or enrich the experiences of these animals,” says Gattas. “This then gives me a gradual measure of how cognitive reserve can lead to a change in the neural activity. In the end, I expect to see some difference that helps me identify a very smart brain from a very naïve brain.”

While her study is still in the early stages, the results could have implications for Alzheimer’s disease in the future.

“If we can quantify what the neural activity looks like in a brain with high cognitive reserve, this could inform how deep brain stimulation can be used as treatment for Alzheimer’s disease,” she says.

While UCI also has two-photon imaging systems, the CCBN lab is already set up for running mice in the virtual reality system, allowing her to get a big head start on her research by coming to the U of L. At the end of September, she will have an armload of data and analysis completed. She will have a perspective of the direction of the study before starting her PhD coursework in Irvine.

“Getting good quality data and having access to the resources, which we do have here, is a big benefit,” says Gattas. “What’s neat about the CCBN is that all the labs are together in one place and they’re all asking different questions. People come from all over the world to study here. Bringing all that together in one building is mentally stimulating.”

Dr. Ivan Skelin observes memories in the making

The partnership between the U of L and UCI has also benefitted Dr. Ivan Skelin, who has a medical degree obtained in his homeland of Croatia. He wanted to combine clinical work with research into how memories are formed. He began doctoral studies at the ��Ѹ��Դ��߿�Ƭ of Zagreb and completed much of the work at Montreal’s McGill ��Ѹ��Դ��߿�Ƭ, where he first heard about McNaughton’s work. After completing his PhD, he came to the U of L to do post-doctoral work with funding from Alberta Innovates Health Solutions.

Dr. Ivan Skelin, a U of L post-doctoral fellow, has been researching memory formation at UCI.

The U of L’s partnership with UCI gave Skelin an opportunity to conduct research in the UC Irvine Health Comprehensive Epilepsy Program, in collaboration with the program’s director, Dr. Jack Lin. He works with patients who have exhausted all treatment options except surgery to remove the part of the brain where the seizures occur. To locate the appropriate area for surgery, surgeons insert electrodes both directly on the cortical surface and deep into the brain.

“Most of the human electrical activity recordings these days are done using scalp electroencephalography, which provides low-resolution, summed activity of large populations of neurons scattered over multiple brain structures,” says Skelin. “We are recording the activity of single neurons — functional units of brain computation — from the electrodes placed directly inside the brain structures relevant for memory formation and retrieval. The big advantage of this approach is that you can correlate the human subjective experience with recorded brain activity.”

Skelin can observe how memories are encoded and retrieved by asking patients to recall a short five-second video they’ve watched and comparing the activity evoked by recall with activity present at the time of memory formation. As the memory-consolidation process of gradual strengthening of selected memories occurs during sleep, overnight recordings allow Skelin to follow the dynamics of memory traces during sleep. Bit by bit, Skelin is mapping the spatiotemporal dynamics of memory in the human brain.

Without the U of L’s partnership with UCI, Skelin would not have had the chance to record directly from the human brain.

“UCI is one of a handful of places in the world where we have the ability to record single neurons from the human brain,” says Skelin. “This is a unique opportunity that I am extremely grateful for. My experiences here have contributed a lot to my career.”

Partnership gaining strength amid future uncertainty

The momentum has been building since the Polaris award began, especially over the past two to three years. Thanks to an NSERC (Natural Sciences and Engineering Research Council) Collaborative Research and Training Experience Program grant, we have been able to support excellent trainees and, with additional support from CFI (Canada Foundation for Innovation), the CCBN has advanced supercomputing equipment, microscopes and electrophysiology setups. Several trainees have gone to attend workshops and training camps in European labs through the Polaris award. The partnership is also enabling new collaborations for CCBN faculty who have had opportunities to spend time at UCI. So far, Drs. Robert Sutherland and Mohajerani have taken advantage of visits to UCI. UCI hosted a joint meeting with CCBN, ��Ѹ��Դ��߿�Ƭ of Alberta and ��Ѹ��Դ��߿�Ƭ of Toronto faculty members to develop a strategic plan for collaborative research projects.

As McNaughton looks ahead to the time when the Polaris award, which is non-renewable, will finish in 2018, his brows furrow.

“I am deeply concerned about what happens then because we will be going from a budget that’s supported about 40 trainees and staff to what can be supported on a regular NSERC grant. We have acquired world-class instrumentation and infrastructure, and are just reaching our peak productivity, but I will have to lay off a lot of people,” says McNaughton. “It won’t end suddenly this time next year because I’ve saved enough in the budget to stretch it another year maybe, a least at a reduced scale, so the door doesn’t slam shut all at once. And, of course, I’m spending a lot of my time applying for other sources of funding, but support for this kind of basic research has been steadily shrinking worldwide. This is a very disturbing trend. Most advances in medicine have, at their root, fundamental discoveries that were made in the context of basic, curiosity-driven scientific research, the impact of which might not be seen in the discoverer’s lifetime. Clinical translation represents the apex of a pyramid, at the base of which is discovery science.”

CCBN research capabilities expand with state-of-the-art optical imaging lab

caroline.zentner — Thu, 23 Jun 2016 16:29:03 +0000

A state-of-the-art optical imaging lab in the Canadian Centre for Behavioural Neuroscience (CCBN) is giving ��Ѹ��Դ��߿�Ƭ of Lethbridge scientists a leg up in unlocking the secrets of how our brains function. Two-and-a-half years in the making, Mohajerani's lab is hoping to map, with outstanding precision, how the brain repairs itself after a stroke and also provide new insight into neurological disorders such as Alzheimer’s disease.

Having an optical imaging facility, along with the establishment of a population of transgenic mice, will allow Dr. Majid Mohajerani and his colleagues to study the mouse brain in action. This modern rodent-imaging facility is the result of a collective effort that began in 2008 with a major investment of Polaris funds from Alberta Innovates: Health Solutions and the U of L to Dr. Bruce McNaughton and with two infrastructure grants from the Canada Foundation for Innovation to Dr. Rob Sutherland.

Transgenic mice look like ordinary mice but they have been genetically modified. They are used in research because they carry many of the same genes as humans and can be used to study many illnesses, including neurological diseases.

“We know that some of the human brain disorders are caused by a variation or a mutation in a gene or group of genes. In the past 30 years, researchers began to insert human genes into the brain cells of living mice," says Mohajerani. "Using transgenic animals, scientists like me can now try to discover the cause of many diseases, and this may point the way to better treatment of those brain disorders."

With these developments, CCBN researchers will now be able to answer more complicated and detailed questions about what goes on in the brain after an injury like a stroke or in neurological diseases like Alzheimer's.

“One of the topics we are interested in studying is the effect of tiny, ischemic (resulting from inadequate blood supply) strokes on cognitive impairment and dementia. This type of stroke is a common feature of the aging brain. In collaboration with Dr. Rob McDonald's lab, we are studying how these small strokes could potentially drive the progression of Alzheimer's pathology and cognitive impairment. Having a transgenic animal model of Alzheimer's disease is essential to address this question," he says. "This work might potentially lead to new understanding of the link between stroke and Alzheimer's disease."

Neurons can be manipulated using genetic tools to fluoresce in different colours when exposed to light, allowing researchers to gain a better picture of what’s happening in the brain.

"Using this novel combination of genetics, optical imaging and bioengineering, we can watch thousands of neurons over the course of days and months. This will allow us to study how different parts of the brain communicate and work with each other, and how changes in brain circuitry can lead to mental disorders like Alzheimer's disease," says Mohajerani. “I have invested a lot of effort to bring our infrastructure to acceptable levels. We can consider ourselves a world-class neuroscience institution."

The equipment allows researchers to shine a light on a specific area in the brain of a transgenic mouse and activate the neurons involved in a particular function or behaviour, such as running or recalling a familiar memory. Not only will Mohajerani’s research program reveal more information about how the brain functions, but the results will also improve treatments for human patients.

“We don’t know whether the findings we make with mice are necessarily translatable to humans but we don’t have any other choice. We have to try different things and hope to see one of them get translated into actual use in humans,” he says.

Mohajerani can now see how the efforts of the past two-and-a-half years are coming together.

“This would not be possible without the talented people who work with me in this department—my colleagues who are very knowledgeable about brain function, our hard-working students and trainees, and our wonderful animal care staff.

Dr. Michael Kyweriga’s auditory research study details some of the work being done in Mohajerani’s lab.

UNews - Dr. Majid Mohajerani

U of L researchers use Alberta Prion Research Institute grant to help unlock molecular mechanisms involved in Alzheimer's disease

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