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Alzheimer’s disease – Canada Brain Power

Canada Brain Power

Tag: Alzheimer’s disease

  • Identification of CD33m as a new protective factor in Alzheimer’s Disease development.

    Identification of CD33m as a new protective factor in Alzheimer’s Disease development.

    Brain Star Award Feature: Ghazaleh Eskandari-Sedighi, University of Alberta, won this prize based on the excellence of the research and its potential benefits to the health of Canadians. Brain Star Awards are presented by the Canadian Association for Neuroscience (CAN) and the Canadian Institutes of Health’s Institute of Neurosciences, Mental Health and Addiction

    Immune cells in the brain, called microglia, are thought to be critical in Alzheimer’s disease (AD) development through numerous functions, including their ability to remove amyloid beta (Aβ), which is protein that accumulates in the brains of AD patients. In this study, Ghazaleh Eskandari-Sedighi, working in Matthew Macauley’s laboratory at the University of Alberta, focused on understanding the mechanism of action of a protein called CD33, which has been identified as one of the top-ranked drivers in the development of AD and that is predominantly found in microglia in the brain. By transferring different versions (called isoforms) of this protein in a mouse model of AD, they were able to show that these different isoforms have opposite effects on microglial cells and AD progression.

    CD33 is a receptor that modulates immune response that exists in two forms:  a long isoform CD33M (Major) and a short isoform: CD33m (minor). Understanding how CD33 isoforms differentially impact microglial cell function has been challenging due to functional divergence between CD33 from mouse and humans. In this study, the researchers introduced the human CD33 gene in a mouse model of AD, which accumulates Aβ protein. In these mice, they found that CD33 isoforms have opposing effects on the response of microglia to Aβ accumulation. The larger CD33M increases the total level of Aβ and formation of plaques with a diffuse nature, which correlates with fewer number of microglia as well as higher number of dysfunctional neurons. In contrast, CD33m gives rise to opposite outcomes; beyond decreasing total Aβ levels, CD33m skews formation of compact Aβ deposits, correlating with increased microglia and fewer dysfunctional neurons. Overall, this work reveals how CD33, as a top genetic susceptibility factor for AD, is connected to microglial cell function.

    Read the full story here: https://can-acn.org/brain-star-award-winnerghazaleh-eskandari-sedighi/

    Scientific publication: Eskandari-Sedighi, G., Crichton, M., Zia, S. et al. Alzheimer’s disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice. Mol Neurodegeneration 19, 42 (2024).

    https://doi.org/10.1186/s13024-024-00734-8

  • Phase 2a clinical trial reveals a small molecule called LM11A-31 is safe and slows progression of many features of Alzheimer’s Disease

    Phase 2a clinical trial reveals a small molecule called LM11A-31 is safe and slows progression of many features of Alzheimer’s Disease

    This is a Brain Star Award feature: Hayley Renee Christine Shanks, Western University, won this prize based on the excellence of the research and its potential benefits to the health of Canadians. Brain Star Awards are presented by the Canadian Association for Neuroscience (CAN) and the Canadian Institutes of Health’s Institute of Neurosciences, Mental Health and Addiction

    Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder for which there is no cure. Therapeutics available to the approximately 734,000 Canadians living with AD provide symptom management without slowing disease progression. Hayley Renee Christine Shanks, working in the laboratory of Dr. Taylor Schmitz at Western University, adopted a novel approach to AD therapeutics by targeting “deep biology” — that is, receptors that control multiple fundamental cellular pathways and may therefore normalize multiple pathological processes underlying AD. This “deep biology” target, called the p75 neurotrophin receptor (p75NTR), plays a critical role in determining  whether cells degenerate or survive. This receptor was discovered approximately 30 years ago and is widely studied in the fields of developmental neuroscience and neurology.

    In AD, p75NTR is a key receptor that mediates neuronal dysfunction, neurodegeneration, and glial reactivity. Research in AD mouse models indicates that modulation of p75NTR with a small molecule called LM11A-31 promotes neuronal resilience and reduces neuroinflammation. Building on this work, Shanks et al. (2024), Nature Medicine, was the first publication to examine selective modulation of p75NTR in individuals with AD.

    Read the full story here: https://can-acn.org/brain-star-award-winner-hayley-renee-christine-shanks/

    Read the original research article here:

    Shanks, HRC, Chen, K, Reiman, EM, Blennow, K, Cummings, JL, Massa, SM, Longo, FM, Börjesson-Hanson, A, Windisch, M, Schmitz, TW. p75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial. Nat Med 30, 1761–1770 (2024).  https://doi.org/10.1038/s41591-024-02977-w

    https://www.nature.com/articles/s41591-024-02977-w

  • Researchers succeed in reversing certain signs of Alzheimer’s in an animal model of the disease

    Researchers succeed in reversing certain signs of Alzheimer’s in an animal model of the disease

    Maintaining an ion pump located in the cell membrane of neurons could slow down or reverse the pathology.

    Text by Jean Hamann – Université Laval nouvelles

    A team of researchers led by Dr. Yves De Koninck Professor at Université Laval and researcher at Université Laval’s CERVO research centre, reports in the journal Brain that they have succeeded in reversing certain cognitive manifestations associated with Alzheimer’s in an animal model of the disease. “Although this has yet to be demonstrated in humans, we believe that the mechanism we have identified constitutes a very interesting therapeutic target because it is not limited to slowing down the progression of the disease, but also makes it possible to partially restore certain cognitive functions,” comments Dr. De Koninck.

    Previous studies have shown that even before the symptoms of Alzheimer’s appear, brain activity is disrupted in people who go on to develop the disease. There is neuronal hyperactivity and a disorganisation of signals in the brain,” explains the researcher. Our hypothesis is that a mechanism that regulates neuronal activity, more specifically the one responsible for inhibiting neuronal signals, is disrupted.”

    The main inhibitor of neuronal signals in the human brain is the neurotransmitter GABA. It works in close collaboration with a cotransporter, KCC2. This is an ion pump, located in the cell membrane, which circulates chloride and potassium ions between the inside and outside of neurons,” explains Professor De Koninck.

    “Whenever 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 neuronal hyperactivity. A study has already shown that levels of KCC2 were reduced in the brains of deceased people who had suffered from Alzheimer’s disease. This gave us the idea of examining 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. In this mouse model of the disease, plaques appear in the brains their abundance increases with age.

    The researchers found that, when the 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 suffering from Alzheimer’s disease. “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, a KCC2 activator which prevents its depletion. Short-term, administration of this molecule to mice that already had reduced levels of KCC2 improved their spatial memory and social behaviour. Long-term, CLP290 protected them against a reduction in cognitive capacity and neuronal hyperactivity.

    “These results do not imply that the loss of KCC2 causes Alzheimer’s disease,” insists Professor De Koninck. “However, it does appear to cause an ion imbalance leading to neuronal hyperactivity that can lead to the death of neurons. This suggests that by preventing the loss of KCC2, we could slow down and perhaps even reverse certain 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 Alzheimer’s sufferers. “We have developed new molecules that are currently being evaluated in our laboratory. In parallel with this research, we are testing drugs used for purposes other than Alzheimer’s in humans to assess their effects on KCC2. Repositioning an existing drug would accelerate work on this new therapeutic avenue,” says the researcher.

    The other authors of the 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.

    Read the original story on the Université Laval website

    Original Research article in the Journal Brain (Open Access): 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, Yves De Koninck, Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer’s disease mutations, Brain, 2023;, awad250, https://doi.org/10.1093/brain/awad250

  • Identification of early markers of Alzheimer’s disease provides opportunities for preventative treatments.

    Identification of early markers of Alzheimer’s disease provides opportunities for preventative treatments.

    The failure of multiple Alzheimer’s disease (AD) clinical trials highlights the need for early markers that accurately identify individuals at risk during the pre-clinical stage before they develop severe symptoms. Within the last decade, spatial navigation deficits have recently emerged as one of the most sensitive behavioral markers of early AD – patients are frequently disoriented and have trouble navigating familiar environments. However, the brain mechanisms that cause these navigational deficits remain a mystery. To shed light on this question at the cellular level, PhD student Johnson Ying from Mark P. Brandon’s Lab at McGill University used thin micron-sized wires to record the brain activity of numerous spatially modulated cell types in a mouse model of AD. In this study, the authors discovered that a specific cell type called “grid cells” in a brain region known as the medial entorhinal cortex were impaired during early pathology.

    Johnson Ying won a CAN-CIHR-INMHA Brain Star award for this discovery.

    Grid cell activity was simultaneously recorded in animals as they freely navigated a square environment. In healthy mice, grid cells became active in multiple spatial locations which formed a hexagonal pattern that tiled the entirety of space – akin to an internal GPS system. In contrast, the hexagonal pattern in AD mice was broken, suggesting that they could not maintain an accurate internal map of space. Grid cell impairments correlated to deficits in a spatial navigation task. All other spatially modulated cell types in the medial entorhinal cortex were unaffected. These results show that early AD pathology does not disrupt all kinds of spatial coding in the brain, but specifically impairs grid cell spatial firing which may underlie navigational deficits in early AD patients.

    These results support the viability of grid cell human fMRI imaging (a brain signal in human beings which is thought to be analogous to grid cells recorded in mice) as an early AD marker that could also be used to assess the efficacy of AD therapeutics administered to patients.

    In parallel, these results further justify the use of spatial navigation tests as sensitive behavioral markers of early AD which the clinical field is much in need of.

    There is no cure for AD. Multiple AD clinical trials in the past have failed to effectively reverse the damage caused by AD in symptomatic patients. The discovery described here has the potential to help identify AD patients during the early stages of pathology, thus providing clinicians and scientists with opportunities to develop therapies that prevent or delay the appearance of severe disease symptoms such as memory loss.

    This work involved recording over 4000 neurons in 68 animals and took 4 years to complete. In all AD mouse model studies to date, this is not only the largest single-unit electrophysiological data set, but the only data set to investigate progressive cellular decline during early pathology. Johnson Ying also collected behavioural data, performed statistical analyses, and wrote the manuscript with his supervisor.

    About Johnson Ying

    Prior to university, Johnson was highly untalented at rote memorization, multiple choice exams (still is), and performed terribly in his biology courses. The thought of one day studying a biological organ was the furthest thing from his mind. Undecided about his future, Johnson stumbled across neuroscience by complete chance when reading a self-help book that talked about neuroplasticity. The fact that a 3-pound lump of jelly governs one’s thoughts, actions, and emotions fascinated Johnson and he knew that he had found his calling. An impulsive decision to study neuroscience turned into a Ph.D. degree under the mentorship of Dr. Brandon who Johnson crossed paths with during undergrad. Johnson attributes his success to Dr. Brandon for taking a chance on a kid with a lot of heart but no direction, support from lab members, funding from FRQS and CIHR, and his parents who worked tireless as first-generation immigrants. Johnson hopes that his story inspires other young minds who are still undecided about their futures or who may not be the best classroom performers to give research a try. After all, in the laboratory, talent and grades matter to much lesser degrees than passion and an honest work ethic.

    Funding sources

    This work was funded by CIHR Project Grants #367017 and #377074, an NSERC Discovery Grant #74105, a Scottish Rite Charitable Foundation Grant, a Canada Fund for Innovation Grant, and a Canada Research Chairs award to Mark P. Brandon. Johnson Ying was supported by a Doctoral Training Grant from the Fonds de recherche du Québec, and previously by a Master’s Training Grant from the Fonds de recherche du Québec and a CIHR Master’s Training Fellowship.

    Scientific publication:

    Ying, J. Keinath, A.T. Lavoie, R. Vigneault, E. Mestikawy, S.E. Brandon, M.P. (2022) Disruption of the grid cell network in a mouse model of early Alzheimer’s disease. Nat. Commun. 13, 886.

    https://www.nature.com/articles/s41467-022-28551-x

  • The latest weapon against Alzheimer’s disease could be as simple as touch

    The latest weapon against Alzheimer’s disease could be as simple as touch

    A study by a team of University of Lethbridge neuroscientists has shown that tactile stimulation shows much promise as a non-invasive method of slowing the onset of dementia in aging mice and could be an additional therapeutic intervention for people with Alzheimer’s disease.

    January is Alzheimer’s Awareness Month and the Alzheimer Society encourages everyone to learn more about dementia and its impact on Canadians. Alzheimer’s disease (AD) is the most common form of dementia and represents a global health crisis.

    Current treatment options only serve to slow the progression of the disease, not to cure or prevent it. That’s why researchers at the Canadian Centre for Behavioural Neuroscience are working hard to increase knowledge about what happens in the brain with AD and find more therapeutic treatments. A recent study by Drs. Bryan Kolb, Majid Mohajerani and their team points the way to a possible easily accessible treatment for AD in humans. Working with a mouse model of AD, the researchers found that tactile stimulation (TS) in the form of light massaging slowed the onset of AD.

    Read the full story on the University of Lethbridge website

  • Offering a new hypothesis for the cause of Alzheimer’s disease

    Offering a new hypothesis for the cause of Alzheimer’s disease

    Alzheimer’s is a complex neurodegenerative disease affecting millions of people worldwide. Yet despite extensive research, our understanding of why the disease leads to cognitive decline and memory loss remains incomplete. Now, researchers in the University of Victoria’s Division of Medical Sciences have published an article in Nature Communications that could critically improve our understanding of what causes Alzheimer’s disease.

    Many well-accepted explanations of the disease include oxidative stress, inflammation, and the buildup of protein clumps (e.g., of amyloid-beta and tau). However, in the new paper, first-author and MSc student Victor Lau (Tremblay Lab), Dr. Leanne Ramer (Simon Fraser University), and senior author Dr. Marie-Ève Tremblay propose a new hypothesis: the progression of Alzheimer’s disease must involve maladaptive, senescent cell buildup.

    Read the full story on the University of Victoria website

  • CIHR Health Research in Action: Better sleep may lead to a better fight against Alzheimer’s disease

    CIHR Health Research in Action: Better sleep may lead to a better fight against Alzheimer’s disease

    Research team at Université de Montréal offers insights that may help both detect and treat the disease among patients in the future

    Issue

    More than 750,000 Canadians are living with Alzheimer’s disease (AD). This complex neurodegenerative condition destroys brain cells and causes a gradual deterioration of memory and thinking.

    Research

    A key feature of AD is the development of plaques composed of amyloid beta proteins inside the brain. Researchers at Université de Montréal are studying how fragments of these proteins initially affect neurons in the hippocampus, which blocks communication between neurons and disrupt sleep patterns.

    Impact

    This research could provide new ways to diagnose and monitor the progression of AD. It may also support the use of new interventions that help improve sleep as a treatment for the disease.

    Read the full story on the CIHR website

     

  • UCalgary researchers use computer modelling to simulate impact of Alzheimer’s on the brain

    UCalgary researchers use computer modelling to simulate impact of Alzheimer’s on the brain

    New way to model neural disease could lead to better understanding

    Author: Shea Coburn, Hotchkiss Brain Institute

    A deep neural network is a computerized brain-inspired machine learning model, which uses many layers of simulated neurons to mimic the function of the cerebral cortex. Each layer in the network creates more complex activity, which simulates the way information is processed in the human brain. These networks can be designed to replicate structures in the brain, allowing researchers and scientists to model specific brain functions more easily.

    University of Calgary researchers have taken a new approach to using these networks for modelling of the human brain. Most studies, to date, have used deep neural networks to look at healthy brain function. These investigators wanted to know if these models could be applied to better understand brain function in a diseased brain. In this case, looking at posterior cortical atrophy (PCA), an atypical form of Alzheimer’s disease affecting the visual cortex.

    “Using these artificial networks to model dementia could enable an improved understanding of the disease,” says Dr. Nils Forkert, PhD, an associate professor in the Cumming School of Medicine and principal investigator. “It allows us to have one well-established reference model that can be damaged in many different ways versus having to image hundreds of patients with different neurodegeneration patterns to obtain similar information.”

    In the findings published in Frontiers in Neuroinformatics, Forkert, along with Dr. Anup Tuladhar, PhD, Dr. Zahinoor Ismail, MD, and PhD student Jasmine A. Moore used a standard neural network for automatic object recognition in images, titled VGG19, to simulate a brain with dementia symptoms. The researchers progressively damaged connections between neurons in the network, to mimic neurodegeneration in the visual system of the human brain.

    Read the full story on the University of Calgary website