Reporting in Science Translational Medicine, researchers write that amyloid-forming proteins, traditionally thought of as enemies to the nervous system, may actually be protective 'guardians' instead. Study author Lawrence Steinman, a neurologist at Stanford University, explains how amyloid injections helped paralyzed mice with a multiple-sclerosis-like disease walk again.
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IRA FLATOW, HOST:
This is SCIENCE FRIDAY. I'm Ira Flatow. Every good story has a villain, right, and in this case, in the case of Alzheimer's, one of the most notorious villains is amyloid plaque. You've heard about it. It's that sticky, gummy buildup thought to be harmful to the brain. But is amyloid really harmful, or is it just an innocent bystander, a witness to the disease?
A study out this week suggests we've got it all wrong, that amyloid isn't really a villain but might be, instead, be a protective guardian of sorts for the nervous system because when researchers injected amyloid into paralyzed mice, victims of a mouse version of multiple sclerosis, these paralyzed mice walked again.
Is it possible that we've just misunderstood the role of amyloid plaque? What could this mean for the treatment of Alzheimer's, Parkinson's, multiple sclerosis? Joining me now to talk about it is Larry Steinman, professor of neurology at Stanford in California, and author of the mouse study, out this week, in the journal Science Translational Medicine. Welcome to SCIENCE FRIDAY, Dr. Steinman.
LARRY STEINMAN: Hello, Ira.
FLATOW: Hi there. Tell us exactly what you did.
STEINMAN: Well, we found that there were deposits of multiple sclerosis brains a few years ago, and we decided to ask when we administered these amyloid molecules, would it make the mouse model of multiple sclerosis worse. That was our hypothesis because we knew that the molecules are supposed to be villains.
Much to our surprise, we found that when we administered them to mice who were paralyzed, they were able to walk around. And as long as we continued to administer these molecules on a daily basis, intravenously, we found that they were perfectly fine. When we stopped giving it, the paralysis recurred.
FLATOW: That's exactly the opposite, as you say, of what you would have expected given the villainous nature of these amyloid plaques.
STEINMAN: Yes, the first time we saw it we thought there must be a mistake, that the cages were switched. But we took a careful look, repeated the experiment, of course, and the finding was quite solid.
FLATOW: How come - then there must be some reason that scientists have been thinking and have given amyloid this bad name, the plaques? Are you convinced that it should - that the villainous aspects should be removed now?
STEINMAN: Well, I spend a lot of time teaching medical students, and I am impressed by the large body of evidence that associates amyloid with diseases like Alzheimer's. And my full expectation in the experiment was that we would achieve the opposite result.
So when we saw the anomaly, it became apparent to us that perhaps, those amyloid deposits in diseases like Alzheimer's and the amyloid that we see in diseases like multiple sclerosis may be playing another role, and that role may be the opposite of what we expected.
It turns out in many cases that the anomaly in the data is more interesting than the impressions that you have of its role from the foundations of the whole theory. So we're looking for the black swans and the outliers to teach us something important, and they very well may.
FLATOW: Have there been clinical trials to get rid of amyloid in the brain and find out that way?
STEINMAN: Yes, there have been about six major clinical trials trying to get rid of amyloid by either giving antibodies or by inhibiting the enzymes that lead to the formation of amyloid, these are trials in Alzheimer's disease. And in each case the trials have failed. A lot of money has been invested, a lot of hopes have been raised, but so far the outcomes have been astonishingly negative, and in some cases there's even indications of worsening of the dementia.
FLATOW: And is this only in mice or in people?
STEINMAN: This is in people that I'm talking about. So one wonders after seeing the empirical results that perhaps there are fallacies in the theory, but there's a large group of scientists and a large body of force that's trying to stick to the idea in the face of negative evidence.
Of course we were looking at a model of a different disease where you see amyloid deposits, and that disease is multiple sclerosis. And I should say that treating mice and reversing paralysis in multiple sclerosis with a particular experimental drug sometimes leads to an approved therapy because we had such an experience back in our lab 20 years ago, when we identified a molecule of interest that was involved in the inflammation of mouse brains with a mouse model of MS, and it led to the most powerful approved drug for multiple sclerosis to date.
FLATOW: So you think you now have a better treatment, then, for multiple sclerosis?
STEINMAN: Well, we might. We're very keen on moving this forward and testing these types of approaches in humans. There are still a number of steps to do before we get there because of the fear of these types of molecules. But I should add that amyloid is a common chemical structure. It's also the name of one of the amyloid-forming molecules.
The others are also associated with villainous roles, how protein, prion protein - they're all associated with bad diseases. Yet in every cell in our body, including our brain, we're making amyloid, and we're making prion, and we're making tao(ph) proteins. So we're wondering what their normal roles be.
Another molecule that we see that forms amyloid structures is called alpha B-crystallin. And it's the major structure in the lens of the eye, which is well-known as an area where it's very hard to induce inflammation. And for the last five years we've been developed an amyloid-based drug, based on alpha B-crystallin, that we intend to try in multiple sclerosis patients.
Someone in Holland has already taken this approach, and so far it's looking safe.
FLATOW: And so the reasoning, if I understand you correctly, is that instead of being the villain here, amyloid may be trying to rescue any kind of or protect any kind of damage.
STEINMAN: Well, that's the hope, and stranger things have happened that the anomaly turns out to be the more interesting part of the theory than the actual theory itself. So we'll see over time, and we'll be driven by experimental results.
FLATOW: President Obama announced this week his Brain iative. Would some of that money go towards studying these connections and the connections to amyloid that you study? Would it be a good idea to do that? I'm sure you would never turn the money down. But is that a ripe area to do research?
STEINMAN: Yes, I think that part of the brain mapping initiative will certainly engage the chemical pathways in the brain. So we're interested in not only the roadmap of what neuron connects to what location but what chemicals are being produced around those pathways and how in certain diseases, whether it's Alzheimer's or schizophrenia or multiple sclerosis, the chemicals cause a disturbance leading to a serious disease.
I think the initiative is going to be very helpful in helping to solve these problems.
FLATOW: One last question about your new potential treatment using amyloid for multiple sclerosis. How far along - are we in phase one, have we got phase one studies, or have we not even gotten that far yet?
STEINMAN: On this one we haven't reached phase one yet. We're still doing the toxicity testing. We're moving slowly because of the villainous reputation of these proteins. But as I said, someone over in Holland has taken this through phase one, and it looks - looks pretty good. They're doing it with alpha B-crystallin.
FLATOW: Well very interesting. Thank you, Dr. Steinman, for taking time to be with us today. We'll be following this.
STEINMAN: Thank you, Ira.
FLATOW: You're welcome, Larry Steinman, professor of neurology at Stanford University in California. Transcript provided by NPR, Copyright NPR.