Award Partner: CLEAR Foundation

The role of Inflammatory bowel disease in the development of Alzheimer’s disease

People with inflammatory bowel disease (IBD) are six times as likely to develop Alzheimer’s disease and on average seven years sooner than people without IBD. IBD will affect 1 percent of Canadians in the next 10 years and there is no cure for this illness. IBD causes intestinal microbiome, neural, immune, and endocrine dysregulation, but the exact mechanisms that drive the development of Alzheimer’s and other dementias are unknown.

 

The goal of my research is to elucidate the mechanisms by which IBD increases the risk of Alzheimer’s and dementia with the long-term goal of developing pharmacological interventions.

Developing sensors for rapid detection of biomarker proteins for Alzheimer’s disease

Dementia is a growing health challenge that affects over 500,000 Canadians today, which is estimated to grow to 900,000 by 2030. Alzheimer’s disease, the most common form of dementia, is characterized by protein misfolding in the brain. This process can start over a decade before the occurrence of significant cognitive decline making it possible to diagnose at an early stage when treatment strategies are most effective. Biomarkers are measurable indicators that help determine if a person may have or be at risk of developing a disease. Researchers have identified phosphorylated tau (p-tau) proteins and small proteins called cytokines to be promising biomarkers for Alzheimer’s disease. To detect these biomarkers in blood samples, very sensitive detection methods are needed but existing methods have drawbacks such as being expensive and time consuming, and need to be performed in a laboratory, limiting their availability to Canadians. We have developed a new sensor that can detect proteins at ultra-low concentrations using a simple and rapid test. Our goal is to make a rapid and easy-to-use tool that can be used by clinicians to help diagnose Alzheimer’s disease and patients for personalized health monitoring.

Resisting Vascular Cognitive Impairment: The Effects of Resistance Training on Myelin and Blood-based Biomarkers of Neuroplasticity in Older Adults

We are studying if strength training exercises can reduce myelin loss and preserve cognitive abilities in adults with cognitive impairment due to vascular risk factors (e.g., high blood pressure), also known as vascular cognitive impairment (VCI).

Worldwide, VCI is the second most common cause of dementia and it is associated with myelin loss. Myelin is a component of neurons critical for transmission of brain signals. Thus, myelin is important for the maintenance of cognitive (i.e., thinking) abilities. Animal studies suggest myelin loss may be minimized with physical exercise. The objective is to determine whether strength training (e.g., lifting weights) is an effective strategy for slowing down myelin loss in persons with VCI.

We will conduct a 12-month study with 88 adults with VCI; half will receive strength training and half will receive balance and stretching exercises. At the end of study, the two groups will be compared on myelin content and cognitive function. Reducing myelin loss could preserve cognitive abilities in adults with VCI and reduce their risk of dementia. Our proposal is also timely as the prevalence and burden of VCI will only increase with the world’s aging population.

Building bespoke artificial cells and tissues on a chip for drug discovery

Human cells are fascinating and complex: they reproduce, break down food to create energy and communicate with each other. The ‘skin’ of the cell, the cell membrane, plays a crucial role in choreographing interactions between a cell and the outside environment, for example by allowing or prohibiting the access of drugs from the cell exterior to the cell interior.

I design and build lab-on-a-chip devices, which are plastic chips the size of a postage stamp inside of which I can manipulate tiny amounts of liquids. I use these lab-on-a-chip devices to create artificial cells to be able to study how the cell membrane regulates access to the cell interior. Human cell membranes have lots of different components that are used to transport drugs into and out of the cell.

Since the cell membrane is complex, we do not always know exactly which component is interacting with the drug molecule, and what effect it has. The cost of developing a new drug is around 2.6 billion USD and a significant proportion of drug candidates fail because we cannot predict how they interact with cells.

My research will help design drugs that can interact with cells more efficiently, so that they can get inside the cell in order to work properly.

Targeting amyloid propagation in Alzheimer disease: Structures, immunology and extracellular vesicle topology

Dr. Neil Cashman is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

As the incidence of Alzheimer’s disease (AD) continues to increase worldwide, a treatment or prevention for AD is a top priority for medical science. One of the main hallmarks of the disease are protein plaques that form inside the brain, and are believed to be the primary cause of brain cell (neuron) death. Research has shown that the protein, amyloid-β (A-beta) is the main component of these plaques.

 

While there are many forms of A-beta produced by brain cells, the specific one that causes AD is hotly debated by scientists. Dr. Neil Cashman, a neuroscientist and neurologist at the University of British Columbia (UBC) has discovered a novel way of identifying a unique form of A-beta that can become toxic and inflict the damage associated with AD.

 

Cashman, who holds the UBC Canada Research Chair in Neurodegeneration and Protein Misfolding, and his team have discovered immunological compounds that specifically recognize the potentially toxic form of the A-beta protein, and can exclusively detect this form in the brains and spinal fluids of AD patients. Furthermore, Cashman found that normal, healthy control patients did not have this dangerous form of A-beta. It was also found that some healthy people naturally develop immune responses against their A-beta oligomer-specific target.

 

Cashman’s team will exploit this knowledge and their unique tools to learn how toxic A-beta proteins can spread from cell-to-cell and region-to-region in the brain causing AD. The discoveries by Cashman’s lab may provide an effective early diagnostic tool for the disease, and ultimately could lead to the development of a preventative vaccine to neutralize the toxicity of abnormal A-beta, potentially slowing or stopping the spread of neurodegeneration in the brain.

 

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

We know that Abeta oligomers, a “seeding species” in Alzheimer’s disease, are predominantly spread in the brain via naked protein aggregates, and not through extracellular vesicles.

 

Why is this knowledge important?

The development of oligomer-specific antibodies (Acumen, ProMIS Neurosciences) has enabled selective immunotherapies for Alzheimer’s disease that target the toxic molecular species of AD, while sparing precursor protein (APP), Abeta monomers, and Abeta fibrils in the form of plaques. Binding to any of these non-oligomer molelcular species of Abeta lead to adverse effects, most prominently plaque-disruption linked ARIA – a form of neurovascular brain edema.

 

What are the next steps?

Dr. Cashman is now the full-time Chief Scientific Officer of ProMIS Neurosciences, which is conducting IND-enabling studies of the oligomer-specfic antibody PMN310. Human phase 1 trials are set for late 2022 or Q1 2023.

 

Publications

Preclinical development of a disease modifying small molecule therapy for Alzheimer disease

Dr. David Vocadlo is leading one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Alzheimer’s disease (AD) is a debilitating and progressive neurodegenerative disease, accounting for almost two-thirds of all dementias in Canada, and in BC affects up to 70,000 people. Symptoms include memory loss, behaviour and personality changes, and a decline in cognitive abilities.

 

Current AD medications treat symptoms of the disease, but none exist that can stop or even slow the progression of AD which starts in the brain many years before it manifests. The need for AD therapies that treat underlying progression of the disease is paramount for the aging population, in particular because of the projected increase in the number of AD patients.

 

Dr. David Vocadlo, a professor in Chemistry and Molecular Biology & Biochemistry and Canada Research Chair in Chemical Biology at Simon Fraser University (SFU), aims to address several key challenges that would clear the way for a promising new AD therapeutic target.

 

The two biological hallmarks of Alzheimer’s disease in the brain, neurofibrillary tangles and amyloid plaques, are caused by the dysfunction and abnormal accumulation of specific proteins that can kill brain cells over time, progressively impairing brain function.

 

Vocadlo and a multidisciplinary group of research teams from SFU, the University of British Columbia (UBC) and the University of York in the UK, are pioneering their new approach that has been shown to block disease progression in animal models of AD by blocking the toxicity of the brain proteins that form the tangles within brains. Their approach centres on a specialized sugar unit called O-GlcNAc. Clumps of protein from AD brains have almost none of this sugar attached to them because the O-GlcNAcase enzyme continues to remove this sugar modification.

 

Vocadlo’s therapeutic goal is to use small molecules to block the activity of the O-GlcNAcase enzyme, and in this way increase the levels of O-GlcNAc in the brain to prevent this protein from clumping together and becoming toxic. Vocadlo’s team is currently advancing this therapeutic target in order to advance it into the clinic.

Locally produced brain insulin in memory and Alzheimer’s disease: A multi-disciplinary approach to a key question

Dr. James Johnson is one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Alzheimer’s disease (AD) – the most common form of dementia – is a fatal, progressive and degenerative disease that destroys brain cells, causing thinking ability and memory to deteriorate.

 

One percent of AD is the early-onset type that runs in families. While extensive studies of these forms of the disease have revealed the genes that cause them, the most common, late-onset forms of AD are understudied and poorly understood at the level required for therapeutic intervention.

 

Studies have shown links between Alzheimer’s disease and obesity, altered fat metabolism, insulin and diabetes, with diabetes increasing the risk of suffering from AD by 30-65 percent. Scientists have also found the brain produces a small amount of insulin with reduced levels in the brains of AD sufferers. While the function of brain insulin is a mystery, evidence suggests reduced brain insulin could play a role in Alzheimer’s disease.

 

Dr. James Johnson, a professor in the Departments of Cellular and Physiological Sciences and Surgery at the University of British Columbia (UBC), further found in preliminary studies that high-fat diets reduced brain insulin production. The goal of Johnson’s continuing research is to answer the key question: is the loss of brain insulin alone enough to cause cognitive impairment? Johnson will test the hypothesis that brain-produced insulin is a critical factor for the survival and function of brain cells in the context of both a genetic change that increases Alzheimer’s risk and a diet that increases Alzheimer’s risk. Using mice models lacking brain insulin, Johnson’s team will assess their ability to learn and study how their brains are reprogrammed. Insulin will be correlated with Alzheimer’s-like changes in human brains.

 

Information on the role and mechanisms of brain insulin through Johnson’s pioneering research has the potential to advance understanding of AD and contribute to an eventual cure. Identifying the link between diet, insulin and Alzheimer’s disease could also enable earlier diagnosis and inform strategies for Alzheimer’s prevention. Furthermore, the findings may shed light on much-needed new drug targets for Alzheimer’s disease or possibly re-purposing existing diabetes drugs.

Novel retinal biomarkers for Alzheimer’s disease

Dr. Faisal Beg is one of five BC researchers supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Millions of people worldwide are afflicted with Alzheimer’s disease (AD). In the absence of a complete understanding of the disease, therapeutic trials have been unsuccessful and there remains no cure. Detecting the onset of AD is difficult as the changes in behavior are subtle and hidden. Biomarkers that can reliably detect AD at the earliest possible stage are essential for disease monitoring and treatment to improve the quality of life for patients.

 

Imaging shows that the brain has a protein called amyloid, which accumulates beyond normal amounts in AD. However, brain imaging exams for amyloid are expensive, can be invasive, and not easily available, and as a result, cannot be used for general screening. Studies suggest that amyloid also accumulates in the retina of individuals with AD, but this has not been proven.

 

Dr. Faisal Beg, a biomedical engineer and professor in the School of Engineering Science at Simon Fraser University (SFU), is leading a multi-disciplinary team of researchers from SFU, the University of British Columbia (UBC) and McGill University to find the connection between the eye and AD by investigating it as a potential source for the earliest biomarkers for the disease.

 

The team is developing computational tools and image processing technologies to examine chemical biomarkers, structural degradation, and functional loss in the eye that may be associated with AD. This work could be the basis for a new retina imaging device using laser light that can show the presence of amyloid in the retina. The technology would improve understanding of the disease mechanisms underlying the accumulation and serve as an early indication that the protein is also accumulating in the brain.

 

Beg’s research could lead to an inexpensive, non-invasive retina exam for use in clinics to screen everyone on a regular basis for the earliest signs of amyloid. Besides having the potential to aid in the early diagnosis of the disease, the imaging techniques may also be able to track the progression of AD and assess the efficacy of treatments under development.

 

Validation of connexins and pannexins as a target for Alzheimer’s disease

Dr. Christian Naus is one of five BC researchers leading teams supported through the British Columbia Alzheimer’s Research Award. Established in 2013 by the Michael Smith Foundation for Health Research (MSFHR), Genome British Columbia (Genome BC), The Pacific Alzheimer Research Foundation (PARF) and Brain Canada, the goal of the $7.5 million fund is to discover the causes of and seek innovative treatments for Alzheimer’s disease and related dementias.

 

Alzheimer’s disease (AD) is the most common form of dementia, accounting for almost two thirds of total cases. There are currently no successful treatments, making the discovery of effective therapeutic interventions critical.

 

The brain contains billions of neurons (nerve cells), and substantially more non-neuronal cells called glia. Astrocytes, the most abundant type of glial cells, closely interact with neurons to control the transmission of electrical impulses within the brain. The major disease hallmark of AD is cognitive decline linked to neuronal wasting, impairment and finally, death.

 

Dr. Christian Naus, a professor in the Department of Cellular and Physiological Sciences at the University of British Columbia (UBC) and Canada Research Chair in Gap Junctions and Neurological Disease, studies the molecular and cellular mechanisms by which astrocytes lose their ability to support neurons that are vulnerable to destruction in Alzheimer’s disease, with the aim to identify new drugs to aid in treatment.

 

Naus’ team examines a unique set of cellular channels in astrocytes and neurons formed by special proteins, called connexins and pannexins. These channels help control the environment in which the cells of the brain must function by allowing a variety of small molecules to pass freely from one cell to another, and allowing them to coordinate cellular responses to various signals. However, when these channels stop working properly, they can become damaging to the environment thus compromising the normal functions of neurons. Naus’ research explores the role of these channels in neurons and astrocytes in order to identify how to manipulate these channels to provide protection for neurons in cases of disease, such as AD.

 

The outcome of these studies will contribute to the potential identification and development of new drugs that will not only target neurons, but also enhance the ability of astrocytes to protect neurons that are vulnerable to cell death in AD.

Elucidating the effect of O-GlcNAc modification on protein stability

The glycosylation of proteins with O-GlcNAc is a ubiquitous post-translational modification found throughout the metazoans. Deregulation of O-GlcNAcylation is implicated in several human diseases including type II diabetes, Alzheimer’s disease, and cancer.

 

However, the basic biochemical roles of O-GlcNAcylation remain largely unanswered. Several recent studies have demonstrated a clear link between O-GlcNAc and cellular thermotolerance.

 

It is likely that a basic function of the O-GlcNAc modification prevents the unfolding or aggregation of target proteins. Dr. King will investigate its role in protein stability through series of biochemical and biophysical experiments to probe the effect of O-GlcNAc on protein unfolding, folding, and aggregation. The results of this research will provide important insights into the basic molecular mechanisms governing O-GlcNAc deregulation in human disease.

 

End of Award Update: July 2022

 

Most exciting outputs

The modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) is a widespread post-translational modification (PTM) that is dysregulated in several human diseases including type II diabetes, Alzheimer’s disease and cancer. However, research progress in this area is hampered by the fact that it is challenging to detect O-GlcNAc on proteins. Further, the basic biochemical roles of O-GlcNAcylation remain largely unanswered.

 

Therefore, we developed a mass spectrometry based method to precisely map sites of O-GlcNAc on proteins. This method employs a UV laser to produce a diversity of O-GlcNAc retained fragment ions, enabling mapping protein modification sites with unprecedented precision.

 

We then explored the role of O-GlcNAc as a biochemical regulator of protein stability. We developed a new high-throughput approach to profile the effect of O-GlcNAc on the thermostability of the proteome. Using this method, we identify several proteins that are regulated by O-GlcNAc. Interestingly, the majority of these proteins display an O-GlcNAc dependent decrease in stability, challenging the prevailing view of O-GlcNAc as being a predominantly stabilizing modification. Thus, we show that O-GlcNAc is a bi-directional regulator of protein stability. We deliver a powerful approach that provides a blueprint for determining the impact of, in principle, any PTM on the thermostability of thousands of proteins in parallel.

 

Impacts so far
This work delivers powerful tools for exploring the role of O-GlcNAc and other labile PTMs as regulators of protein biochemistry.

 

Potential future influence
Decreased levels of protein O-GlcNAcylation is associated with Alzheimer’s disease. However, the basic biochemical mechanisms underlying this association remain unknown. Here we show that O-GlcNAc regulates the stability of several proteins within human cells, a phenomenon that may impact cellular protein levels in Alzheimer’s disease. This fundamental research is important for understanding the impact O-GlcNAc has on protein structure and stability, particularly in the context of its dysregulation in neurodegenerative disorders.

 

Next steps
We plan to continue exploring the influence O-GlcNAc has on protein structure and function. In doing so, we hope to improve our understanding of the fundamental mechanisms underlying neurodegeneration. This research may ultimately provide knowledge that contributes toward the development of new therapeutic strategies.

 

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