Award Partner: CLEAR Foundation

Alzheimer brain through 3D bioprinting patient-derived stem cells

Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 55 million people worldwide. With no cure or prevention, AD remains a high priority challenge for the Canadian health care system. researchers struggle to develop effective treatments due to poor lab models that do not fully mimic the human brain. This project will create an advanced 3D brain model using patient-derived stem cells to better study early AD stages, focusing on the role of the Amyloid beta protein. By creating a more accurate brain model, this research will help us understand AD more clearly and find new treatment options without the need for animal testing. Findings will be shared widely with stakeholders and patients’ organizations. A group of people with dementia and their caregivers will share their experiences to help guide the research, ensuring it stays patient-focused and promotes mutual learning.

Unraveling Apolipoprotein E’s Role in Alzheimer’s Disease: Insights into miRNA & Glial Regulation and Amyloid Pathology.

• Alzheimer’s disease (AD) is a brain disorder that some people develop as they age. It affects memory and thinking. A protein called ApoE is important in managing fats in the body and supporting brain health. An abnormal variant of APOE4, increases the risk of developing Alzheimer’s, but scientists don’t know why.
• Research shows that mice without ApoE or with human APOE4, and humans with APOE4, have similar problems with fat metabolism, memory, and brain health. Since the retina, the light-sensitive layer at the back of the eye, connects directly to the brain, studying it can provide important clues about how Alzheimer’s affects the brain.
• We will analyze brain, retina, and tear samples from mice without ApoE and those with human APOE4 to look for cell-level changes linked to inflammation, harmful protein buildup, and nerve damage. Tear samples from AD patients with and without APOE4 will also be studied. Results will be shared through workshops, scientific papers, and policy briefs.
• Our goal is to identify early warning signs of AD and understand how ApoE contributes to brain and eye damage. The findings may lead to simple, risk-free tear tests for early AD detection and inspire new treatments targeting ApoE pathways.

The role of acquired brain injury in amplifying dementia risk through modifiable factors

Acquired brain injuries (ABIs) like traumatic brain injury or stroke can cause long-term issues with thinking, mood, and daily life. They also increase dementia risk, but we still do not fully understand how or how best to prevent it. This research fills that gap by exploring how ABIs worsen known dementia risks (e.g., high blood pressure, depression, inactivity) and by studying blood markers of early brain damage and inflammation.

I will use large Canadian health studies to track how ABIs affect dementia risk over time and identify unique risk factors. We will also follow people recovering from a recent ABI, measuring these biomarkers and lifestyle factors to learn how they speed—or slow—brain changes linked to dementia.

I will share our findings through plain-language briefs, workshops, and online resources with healthcare providers, policymakers, and people living with ABIs. Ultimately, this project will guide new prevention strategies and create a clinical decision-support tool to help doctors spot those at highest risk. Tailored interventions based on these results could lower dementia rates and improve long-term care for ABI survivors.

3D bioprinting patient-derived neural tissues for screening potential treatments for Alzheimer’s disease.

Alzheimer’s disease (AD) is the most common form of dementia and continues to affect more people globally due to the aging population. AD currently has no treatment or prevention options aside from symptom alleviation, making it a high priority in medical research. Despite years of research, no AD treatments have been discovered since most studies have used tissue replicas (or models) that do not accurately act like the brain. This has led to presumed success of treatments in research, but failure in clinical testing in animal models. The use of three-dimensional (3D) models that contain brain cells organized in a more accurate 3D structure will allow for a better understanding of AD, which is the focus of this work. In addition, these 3D models can include patient cells to provide specific treatment options for those with AD. The patient-specific AD models will be used to test various drugs, including those with current approval for other diseases. The proposed research will provide new insight into AD treatments by using more accurate AD models to better understand this complex disease in research. The 3D tissue models will allow for better screening of treatment options, ultimately bringing us closer to finding a cure for AD.

Quantifying navigational impairments in preclinical Alzheimer’s disease

Our brain contains a ‘cognitive map’ of the external world that helps us navigate, and encode/retrieve memories. Dementias such as Alzheimer’s Disease (AD) degenerate these regions, causing well-known memory impairments and much less well-understood navigational impairments. My research program seeks to quantify how navigation is impacted in early AD in rodents and humans.

Young and older human participants will navigate a virtual reality maze. We will quantify how their errors in positioning and navigating scale when the complexity of the task is increased. We will perform similar experiments in rats navigating a physical maze, where we can additionally record neural activity. We will then extend the task to participants diagnosed with preclinical AD, and rodent models of AD. We will characterize the behavioural and neural correlates of early progression of AD, with the goal of finding a metric that is predictive of AD-induced cognitive impairment, and its underlying neural mechanisms.

Over 60,000 British Columbians currently live with dementia. A non-invasive and affordable test such as this will allow clinicians to perform early diagnosis, and start approaches that reduce symptoms and improve quality of life.

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.

End of Award Update – May 2024

Results:
Our main goal in this project was to measure the effect of resistance exercise (e.g., lifting weights) on myelin levels in the white matter. Myelin is the fatty tissue layer that covers axons in the white matter of brain, which is related to faster neuronal signal transmission. Myelin loss is very common in older adults living with cerebral small vessel disease. This condition causes a series alterations in the white matter, which may lead to declines in brain functioning and increase dementia risk. We first showed that higher levels of physical activity (e.g., waking, gardening, etc) were associated with greater levels of myelin in a few important structures in the white matter, including a region called corpus callosum in people with cerebral small vessel disease. We then tested whether 12 months of  the exercise program, resulting in no major changes in myelin. We compared resistance training group to a balance, stretching and toning group. Contrary to our hypothesis, the resistance group did not lead to changes in myelin, but the balance, toning and stretching group resulted in greater myelin levels measured in the deep white matter of the brain. This indicated that for these deep regions, including the fornix and corpus callosum, an exercise program focusing on balance, toning and stretching exercise may benefit myelin. The effects of resistance exercise may be more visible in other regions, which we have not yet looked in this study. Candidate regions include those that are linked with important cognitive abilities, such as the anterior cingulate cortex. I am currently investigating changes in these regions.
Impact:
Our research so far has received good attention from the scientific community, with two papers from the project being published in high-quality journals. I have also been able to present the findings from our work at international meetings, wherein I had the opportunity to exchange knowledge and gain new ideas for future projects.
Potential Influence:
The support I received from Health Research BC on this project allowed me to grow as a researcher, teacher, and mentor. The knowledge gained, connections formed, and experiences collected have been crucial in shaping the next steps in my career. This award provided me with the unique opportunity to work with and learn from an internationally recognized researcher and inspiring mentor in Dr. Teresa Liu-Ambrose and incredible co-mentors like Dr. Roger Tam. I also formed meaningful friendships with lab mates and very productive collaborations with colleagues at UBC, across Canada, and at international institutions from places like the US, Germany, and Spain. The Health Research BC award was instrumental in completing my postdoctoral fellowship and will have a long-lasting impact on my career. I am hoping to soon start my own research lab and continue investigating the role of exercise and other lifestyle interventions in promoting brain health and overall healthy aging.
Next Steps:
I will continue to investigate the impact of exercise on myelin and other clinically meaningful outcomes in people with cerebral small vessel disease, working alongside Dr. Liu-Ambrose and Tam at UBC. We are organizing the knowledge translation activities at UBC such as the Brain Health Symposium to take place in the summer. Our work will also be showcased at upcoming Alzheimer’s Association International Conference in Philadelphia. I will present on findings from my postdoctoral research at a Featured Research Session as well as in a Perspective Session, which Dr. Liu-Ambrose and I organized with colleagues from Spain and the US.

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