Exploring the connection between hypoxia and Alzheimer’s disease

11 May 2020

In the battle against the global scourge of Alzheimer’s disease, a neurodegenerative condition, Joseph Wong (Croucher Cambridge International Scholarship 2016) is engineering novel pathways to understanding the role of hypoxia in the disease.

He is doing so by having developed a new lab-based model for investigating the impact of hypoxia on the brain’s white matter, and the molecular mechanisms involved.

Wong knew from a young age that he would become a scientist. He grew up reading books about physics that sparked his fascination with the world around him.

Over the years, his interests have shifted from physics to engineering and eventually to biomedical field, and dementia in particular.

After enrolling at the University of Hong Kong, he began exploring what type of engineering he wanted to specialise in and stumbled across biomedical engineering.

“I had the idea of helping people in the healthcare system, but I didn’t really know what was out there,” Wong explained. “Then I came across people working with prosthetics and regenerative engineering, and that really made me interested.”

Wong began conducting research in Dr Barbara Chan’s laboratory in the Department of Mechanical Engineering. His project was focused on tissue engineering and developing stem cell-based technologies. This included investigating therapeutic methods for osteoarthritis by transplanting stem cells that could differentiate into cartilage cells called chondrocytes.

In 2015, he graduated with a BEng in Medical Engineering. For his postgraduate studies, he knew he wanted to shift his focus to dementia-related research. “I feel like I’ve always been helped by people older than I am,” Wong said. “I think that if their memories are lost, it’s a piece of information that is lost forever.”

Wong joined Dr Lisa Hall’s laboratory at the University of Cambridge, where he completed his MPhil and continued as a PhD student. In 2016, he was awarded a Croucher Cambridge International Scholarship to assist his research.

“The scholarship provided me [with] opportunities to meet top-class researchers across the field from Hong Kong and internationally through its generous support to attend conferences,” Wong said. These included prestigious Gordon Research Conferences.

For his thesis, Wong was interested in studying a type of brain damage that was initially discovered and monitored by magnetic resonance imaging (MRI). MRI uses powerful magnets to take 3D images of the body in a non-invasive manner. Recent advances in MRI technology have enabled new insights into many different diseases.

I think that if their memories are lost, it’s a piece of information that is lost forever.

One such insight was uncovered by scanning the brains of patients with Alzheimer’s disease, the most common form of dementia worldwide. Researchers identified many lesions within the white matter of these patients’ brains, which correlated with the severity of the disease.

White matter contains the signalling tracts that connect different neurons, while grey matter contains the cell bodies of these neurons. “The white matter is highly important for signal transduction,” Wong explained. “It is highly correlated with intelligence. Humans have a higher volume of white matter than most other animals.”

It had previously been thought that Alzheimer’s was primarily driven by amyloid-beta plaques and interneuronal tau tangles resulting in the loss of grey matter. However, the widespread existence of white matter lesions suggested that the white matter actually could be the main contributor to neurodegeneration.

Wong wanted to understand why these lesions appeared much more frequently in the white matter than the grey. He hypothesised that it may be because the white matter tends to be farther from the brain’s blood supply, which could make it more vulnerable to a sudden loss of oxygen (hypoxia).

Oxygen is transported via blood vessels throughout the brain, and its concentration can greatly affect the brain’s function. Among other things, hypoxia can promote the misfolding of amyloid-beta and tau, two toxic proteins that accumulate in the brains of Alzheimer’s patients. Thus, Wong wondered if hypoxia could be responsible for the white matter lesions.

Given that conducting research in humans is highly difficult, Wong sought to create a model that he could study in the laboratory.

Most other labs create a hypoxic environment using incubators, hypoxic chambers, or microfluidic systems. Incubators and hypoxic chambers can take several hours to equilibrate to the correct oxygen concentration. Microfluidic setups work faster but building them can be a complex endeavour.

Wong set out to create a fast and simple system to induce hypoxia. He created an oxygen scavenging setup to incorporate conventional culturing wells, allowing users to create focal hypoxia within a single petri dish of cells and enabling them to study multiple conditions side by side.

The setup reduced the time to reach hypoxia from ambient oxygen levels by more than 95 per cent compared with incubators and hypoxia chambers. Additionally, it facilitated live cell imaging, which means morphological changes of cells can be traced.

Thus, the model allowed Wong to study the effects of hypoxia in a more localised and acute manner than was previously possible.

Now that he has a new hypoxic model system, Wong plans to compare neurons derived from Alzheimer’s and healthy patients to see if they respond differently to hypoxia. He hopes to also incorporate other brain cell types, such as astrocytes, microglia, and oligodendrocytes, to gain a fuller picture of how hypoxic conditions affect the brain.

Wong, who is nearing the end of his PhD studies, is hopeful that by learning about the molecular mechanisms of hypoxia, he may be able to identify proteins or signalling pathways that could be targeted by drug candidates. If administered early enough, such a drug could potentially minimise the damage from hypoxia and prevent the development of Alzheimer’s.

He is also currently applying for postdoctoral positions around the UK. His goal? To continue in the area of Alzheimer’s disease and continue with his passion for scientific research.

Joseph Wong received a BEng in Medical Engineering from the University of Hong Kong in 2015. He earned his MPhil degree from the University of Cambridge, where he is currently a PhD student. His work with Professor Lisa Hall in the Analytical Biotechnology Group aims to create novel biosensors to better understand Alzheimer’s disease and how hypoxia can induce white matter lesions in the brain. He received a Croucher Cambridge International Scholarship in 2016.

To view Wong’s Croucher profile, please click here.