There is a little known fact that the average adult loses about 10 billion cells per day through a process called apoptosis or “cell death”, which is where cells undergo a form of programmed death. Normally, this highly predictable and controlled process is necessary to maintain normal functioning of the human body. For example, during human development in the womb, the fingers of our hand are formed after programmed death of the cells in between them. However, abnormal increases in cell death have been linked to neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Alternatively, decreased cell death can lead to abnormal cell growth and potentially to the development of various cancers.
As such, developing adequate tools to study apoptosis is essential to gain a better understanding of a wide spectrum of human diseases. Until now, no adequate method existed to study this process in living beings, where early detection of abnormal cell death could mean major advances in the treatment of neurodegenerative diseases. A multi-disciplinary team of researchers led by Marco Prado and Robert Bartha from the Robarts Research Institute at Western University have been able to accomplish exactly this. In their recently published work in the journal Contrast Media and Molecular Imaging, the team developed a radioactive molecule called a ‘tracer’ which is almost exclusively retained in cells undergoing apoptosis.
Example of PET imaging using a glucose tracer in the brain of an Alzheimer’s disease patient. Areas in red have the highest glucose uptake while blue depicts the lowest.
This tracer, which functions like a neon sign pointing directly at these cells, makes them visible using the widely available positron-emission tomography (PET) scanner. Dying cells can be observed as a bright highlighted area using this technology (see image for an example), which is already widely used in the hospital setting for testing heart function, brain function and to help locate and identify tumours. PET can also be combined with other imaging techniques to simultaneously obtain information about human anatomy. This combination of techniques can provide a promising collection of data that will be useful in the development of novel clinical approaches.
Thus far, the researchers showed that cells undergoing programmed cell death are efficiently labelled by the tracer. They performed experiments using brain cell cultures, brain cells that have been grown under controlled conditions that mimic those in the body (optimal temperature, pressure, supply of important nutrients, etc.). The researchers exposed those cultures first to a compound that directly induced cell death and to two forms of physiological stress that mimic the conditions in stroke and Alzheimer’s disease (both of which induce apoptosis). Keep in mind that physiological stress is different from the types of stress that you and I may be more familiar with in our day-to-day (hopefully not too familiar!), like when work deadlines are approaching. For the stress imitating stroke, brain cell cultures were deprived of glucose and oxygen, two essential elements to sustain life, which led to cell death. In the second form of stress, the cultured cells were exposed to a protein that is typically associated with Alzheimer’s disease, which also led to cell death.
Amazingly, the tracer labelled dying cells in all three conditions. This led the researchers to try it in animal models of stroke and Alzheimer’s disease. Again, the tracer allowed clear identification of the loss of brain cells in areas that are typically associated with these disorders, while the animals were still alive.
Taken together, the results of this teams’ work hold promise for applications to many human conditions, including earlier diagnosis of neurodegenerative diseases based on the location of cell death or to measure the effect of treatments on apoptosis. For example, the authors suggested that this tracer could be used to see the impact of cancer treatments on tumours, where an increase in signal from the tracer would indicate that the cancer cells are dying as hoped. However, despite the tracer not showing any negative side effects in the brain cells or in the animals used during this study, it will be very important to ensure safety in humans before we can hope to use it. This important work brings us much closer to seeing that reality.
Original Research Article: Ostapchenko, V. G., Snir, J., Suchy, M., Fan, J., Cobb, M. R., Chronik, B. A., … Bartha, R. (2019). Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer’s Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [68Ga]Ga-TC3-OGDOTA. Contrast media & molecular imaging, 2019, 6403274. doi:10.1155/2019/6403274
- Renehan AG, Booth C, Potten CS. What is apoptosis, and why is it important? BMJ. 2001;322(7301):1536-1538. doi:10.1136/bmj.322.7301.1536