Swimming against the current in Alzheimer's disease research
This week I got to sit down with my mentor, Dr Carol Colton, to talk about her experiences in Alzheimer’s disease research. The exciting research that has been more successful at waking me up in the morning than a SonicBoom alarm clock started 25 years ago as an idea – an apple that fell from a tree! Hearing about the latest philosophies in the world of AD from Dr Colton has been nothing short of eye-opening. Given the enormous impact of AD on our economy and healthcare system – an impact that is only going to increase as the population ages – as well as the utter lack of treatments available despite years and millions of dollars of research, the present does seem like a good time to step back and evaluate the prevailing Amyloid Theory.
Q: Did you always know that you wanted to be a researcher?
A: I knew that I wanted to be a scientist when I was 9 years old. I was interested in how things work, how plants grow…. I was very much interested in biology.
Q: Where did you go for your undergraduate studies? What did you major in?
A: I did my undergraduate studies at Eckerd College and I majored in zoology. After that I went to UCL for a year. I studied physiology for my post grad. Physiology is very good discipline because it shows you how things are supposed to work.
Q: How did you get involved with Alzheimer’s disease and neuroimmunology?
A: Very few people studied microglia right after they were “rediscovered” in 1987. I had been studying oxidation and redox biology – how oxygen affects the brains and neurons, etc. – and I found that synaptic transmission was sensitive to high oxygen. We could block LTP (long term potentiation) with oxygen at high pressure, and this leads to seizures. At ths time, people did not think much about oxidation in the brain. But this made me think about whether there is a source of oxidative stress in the brain. NADPH, a macrophage protein, was discovered. So I asked: Is there a macrophage in the brain? I knew that proteins associated with oxidative stress were altered in Alzheimer’s disease. So it got to the point where I thought: Microglia could be the cause of damage in Alzheimer’s disease!
[Microglia are the resident macrophages of the brain and spinal cord, and thus act as the first form of immune defense in the central nervous system. Microglia secrete large amounts of hydrogen peroxide and nitric oxide as part of the inflammatory response. Both of these chemicals can damage neurons and lead to neuronal death.]
I distinctly remember the day that this dawned on me. I have been doing this now for 25 years. It’s the perfect example of how you can become really intriguied by an idea. It was like a light bulb had gone off. You have an insight and then you ask: What if that’s true? And how do I study it?
At that time nobody knew what microglia were. The people at NIH (where I was working) were throwing away their microglia. So I went upstairs, and I talked to them, and I asked them if they could give me their microglia. With these microglia I looked for oxidase and superoxide production. Research is all about interaction in some ways…
Q: What are some of the ups and downs of being a researcher?
A: Research is a hard life. But where else do you have the ability to be so creative? The outside world doesn’t really understand that. In research, you can not only be creative, but there is also the practical impact of being able to help somebody or solve some problem. It’s a perfect combination.
Q: How have your views on research changed over the past 25 years?
A: I still think that research is not an easy task. That has not changed. What has changed is probably my degree of cynism for people. There is a lot of unncessary politics in science. The Amyloid Theory is a good example. People may have damaged the field by their refusal to allow for different viewpoints. But the field is slowing coming around. So we will see...
[The Amyloid Theory states that beta-amyloid (the key component of senile plaques) is the initiator of Alzheimer disease pathology. Proponents of the Amyloid Theory have for the most part neglected the role of other proteins (such as tau) and events (such as chronic microglia activation) in the disease process.]