Seeking the roots of dementia, one cell at a time
South African physiologist Ben Loos uses sophisticated images techniques to find the cellular markers of neurodegenerative disease
For the past 13 years, Ben Loos, a physiologist from Stellenbosch University in South Africa, has been trying to understand the role of autophagy in dementia. From the Greek word for ‘self-eating,’ autophagy is a process in which worn out, toxic or degraded cellular components are swept up and recycled.
What if we could understand whether an individual cell was in distress? Would identifying cell distress provide an early warning sign for the onset of neurodegenerative diseases?
Loos uses sophisticated techniques, such as super resolution and correlative microscopy, to peer deep within single cells and visualize molecular markers that can reveal their health, stress and death.
The images provide an accurate, and precise view into the molecular roots of neurodegerative disease. They are also beautiful. In 2020, Loos worked with Stellenbosch University’s Department of Visual Arts to curate a selection of micrograph images that were displayed in an exhibit at the Rupert Museum in 2020. The exhibit was titled Science meets Art: Art addressing stigma in illness.
Loos spoke to Wiida Fourie-Basson about his work investigating living cells, to understand and how they can reveal the unknown processes that underpin neurodegenerative disease.
The cell constantly maintains a homeostatic environment that enables its survival and allows all its functions to take place. In this image, the organelles called autophagosomes (green) remove unwanted materials. These move along a framework of tubulin (red) to reach all corners of the cell. If neurons are not working properly, they cannot communicate with one another effectively, which can lead to memory loss.
What can we determine about dementia on a cellular level?
Alzheimer’s disease is the most common cause of dementia. Neurons die too fast, which leads to cognitive impairment. Alzheimer’s disease is progressive, and the disease burden is significant.
Neurons require large amounts of energy in the form of adenosine triphosphate (ATP), which is primarily produced in the mitochondria. The active nature of mitochondria requires a high protein synthesis rate which, in turn, needs to be matched with a very efficient protein degradation system. It is these two systems, controlling the energetic state and the homeostasis of proteins, that become dysfunctional in Alzheimer’s disease.
Neurons are terminally differentiated. They do not divide or regenerate like other cells. Any glitch in the protein degradation control and mitochondrial function processes may lead to the premature death of neuronal cells, and ultimately cognitive impairment.
Mitochondria are responsible for supplying neurons with energy (ATP). Healthy mitochondria (red) are polarised. When cells die, this polarization (and red signal) is lost, and we witness the death of the cell. We try to understand why some cells die earlier than others. (This video has no sound)
Mitochondria are responsible for supplying neurons with energy (ATP). Healthy mitochondria (red) are polarised. When cells die, this polarization (and red signal) is lost, and we witness the death of the cell. We try to understand why some cells die earlier than others. (This video has no sound)
The cell is dynamic and responds to changes in its environment. This response is reflected in the movement of its organelles. Here, vesicles (autophagosomes) are transported along a tubulin network. In the past few years, the rate of degradation has been quantified. Micrograph: André du Toit (This video has no sound)
The cell is dynamic and responds to changes in its environment. This response is reflected in the movement of its organelles. Here, vesicles (autophagosomes) are transported along a tubulin network. In the past few years, the rate of degradation has been quantified. Micrograph: André du Toit (This video has no sound)
In Alzheimer's disease, two proteins in the brain, amyloid-beta and Tau, clump together to form amyloid plaques and twisted Tau fibres. These plaques develop during normal ageing, but in Alzheimer’s disease they develop much faster, so more senile plaques would be observable if one would assess the brain post-mortem. Age is the biggest risk factor for the onset of Alzheimer’s disease. The healthier we age, the lower are the chances for the onset of Alzheimer’s disease.
This neuron shows features found in Alzheimer’s disease. Specific proteins aggregate (white structures) and, if not removed will lead to toxicity. This is a very sick cell, on the verge of death. Micrograph: Claudia Ntsapi
These plaques are normally cleared through autophagy, but if there are too many of them, they overburden the autophagy system. The proteins start to aggregate and become toxic. Speeding autophagy up is one of the recent interventions which indicate that it could help the cell to survive.
This neuron shows features found in Alzheimer’s disease. Specific proteins aggregate (white structures) and, if not removed will lead to toxicity. This is a very sick cell, on the verge of death. Micrograph: Claudia Ntsapi
This neuron shows features found in Alzheimer’s disease. Specific proteins aggregate (white structures) and, if not removed will lead to toxicity. This is a very sick cell, on the verge of death. Micrograph: Claudia Ntsapi
Tau stabilizes the road and rail system of the cell. When that stabilization system fails, so too does the cell's ability to move autophagosomes and mitochondria, leaving them to accumulate. This provokes a cascade of dysfunction and forms the root cause of the disease.
To make matters more complex, there is an interplay between Tau and A-beta. Tau stabilises tubulin, which is required for autophagosome and mitochondrial transport. A-beta ‘toxifies' the mitochondria, which makes them less able to generate ATP. With increasing levels of proteotoxicity, an overburdened autophagy system, and dysfunctional mitochondria, the neuron becomes very ill; it will start to lose its function, and finally it will undergo programmed cell death (apoptosis).
Part of the reason we study the living, diseased neuron is to preserve its cellular function. We hope to delay cell death as long as possible. If we can extend that delay years or decades, it could resemble a cure.
The microtubule network becomes impaired in Alzheimer’s disease. It thickens and becomes stiff (right/bottom). A protein called Tau (which stabilises the tubulin network in healthy cells [left/top]), becomes compromised and aggregates. Here, single molecule imaging assisted to super resolve such a dysfunctional neuronal tubulin network. Micrograph: Dumisile Lumkwana
The microtubule network becomes impaired in Alzheimer’s disease. It thickens and becomes stiff (right/bottom). A protein called Tau (which stabilises the tubulin network in healthy cells [left/top]), becomes compromised and aggregates. Here, single molecule imaging assisted to super resolve such a dysfunctional neuronal tubulin network. Micrograph: Dumisile Lumkwana
The cell’s mitochondria (red) are degraded by engaging with autophagosomes (green) when it becomes old and dysfunctional.
The cell’s mitochondria (red) are degraded by engaging with autophagosomes (green) when it becomes old and dysfunctional.
Mitochondria are the cell’s organelles that produce energy (ATP). These structures are visible as dynamic networks. Micrograph: Jurgen Kriel
Mitochondria are the cell’s organelles that produce energy (ATP). These structures are visible as dynamic networks. Micrograph: Jurgen Kriel
Dysfunctional mitochondria (yellow) are specifically selected and removed from the healthy mitochondria (blue) to ensure a maximal energetic state of the cell. Micrograph: Sholto de Wet
Dysfunctional mitochondria (yellow) are specifically selected and removed from the healthy mitochondria (blue) to ensure a maximal energetic state of the cell. Micrograph: Sholto de Wet
The cell is the smallest living responsive and dynamic entity. Once you have appreciated that, under the microscope, you don’t want to go back to anything that does not capture this dynamic behaviour. In this image, cells communicate with one another and exchange signals. This is how the microenvironment is constantly assessed.
The cell is in constant change, spreading out, adhering, detaching, moving, and spreading out again.
“Science meets art” to address stigma in illness
Postgraduate students in my research group wanted to help communities understand mental illness and neurodegeneration. Often, the scientific nomenclature for these diseases does not exist in African languages, or their African names are unknown, making communication a particular challenge.
We worked with Stellenbosch University’s Department of Visual Arts to curate a selection of micrograph images of cells and cell processes associated with neurodegenerative diseases. Through the Rupert Museum, six local artists were commissioned to interpret the micrographs through mediums such as bead work and paper. The exhibit Science meets Art: Art addressing stigma in illness went on display in the Rupert Museum in October 2020, with explanations of the micrographs and accompanying artworks in English and isiXhosa. The artworks became an entry point to discuss symptoms such as depression and forgetfulness, associated with mental illnesses such as dementia, with communities.
A dense microtubule network (red) allows the cell to transport material that needs to be removed. The green signal shows mitochondria, the powerhouse of the cell, providing energy. Credit: André du Toit
Beadwork necklace, called Isiyaca, by Zingisa Vula. Traditionally worn at social events, weddings, and functions. Image: Elmarie Costandius
One aspect quite close to my heart, is how this imaging work over the years has resulted in a small but growing bio-imaging hub here at Stellenbosch University. This has led to the establishment of South Africa Bioimaging, to combat resource limitations by sharing know-how and transferring skills across the country.
This article is part of Nature Africa’s ongoing collection on dementia in Africa, which includes both journalism and free research papers.
A dense microtubule network (red) allows the cell to transport material that needs to be removed. The green signal shows mitochondria, the powerhouse of the cell, providing energy. Credit: André du Toit
A dense microtubule network (red) allows the cell to transport material that needs to be removed. The green signal shows mitochondria, the powerhouse of the cell, providing energy. Credit: André du Toit
Beadwork necklace, called Isiyaca, by Zingisa Vula. Traditionally worn at social events, weddings, and functions. Image: Elmarie Costandius
Beadwork necklace, called Isiyaca, by Zingisa Vula. Traditionally worn at social events, weddings, and functions. Image: Elmarie Costandius
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