NPR Story
12:00 pm
Fri February 3, 2012

Study Tracks Alzheimer's Progression In Mice

Originally published on Fri February 3, 2012 12:40 pm

Transcript

IRA FLATOW, HOST:

Next up, Alzheimer's research. Researchers think they have discovered a key clue to how Alzheimer's spreads in the brain. If you look in the brains of people diagnosed with Alzheimer's, you can see abnormal clumps of cell debris called amyloid plaques and tangles of a protein called tau. And we all have tau proteins in our brains, and we need them to live. But in people with Alzheimer's, the tau proteins take on a new shape, and they form into tangles. But in new work published this week, researchers reported that at least in mice, the tau tangles seemed to spread through the brain as Alzheimer's disease progresses.

It's sort of starting out in one small part of the brain responsible for memory storage, then spreading sort of like a cancer spreads or a virus. Joining me now to talk about the finding is Karen Duff. She's one of the authors of that study in the journal PLOS One, and is professor in the Department of Pathology and Cell Biology at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain. That's part of Columbia University Medical Center here in New York. Welcome to the program.

DR. KAREN DUFF: Thank you. Thank you for having me on the show.

FLATOW: When I made that description, I want to make sure people don't get the idea that it's spreading and it's contagious like a virus.

DUFF: Yes. That's a very important point that we need to clarify, I think. We - when thinking about how to describe what we think is happening to this tau protein in the brain, we wanted a metaphor, an analogy that perhaps would evoke, you know, a sort of visual in people's minds. And so we came - we identified this idea that it was infecting cells, or spreading like a virus. But there's - we don't believe - there is no idea that this is actually spreading to people. You know...

FLATOW: Right.

DUFF: ...your grandmother's not going to sneeze on you, and you'll get Alzheimer's disease. That's not the - that's not what we're trying to say here.

FLATOW: But it is spreading from one cell to the other?

DUFF: Right. So that's the biological understanding that we've gained from making this mouse model of Alzheimer's disease, is that - unexpectedly, what we've seen is that if you can start a pathology, a tangle in one cell, you can actually pick it up in a neighboring cell later on in the disease. And that's sort of spreading by a mechanism we don't fully understand, but it's really an interesting biological phenomenon.

FLATOW: And the - what is spreading? Is it the protein itself that's spreading?

DUFF: Yes. I mean, we - in the experiments that we set up, we actually are monitoring the protein, and it is actually, in some way, getting out of one cell in region A and appearing in a second cell in region B. And that's exactly what you see in a human brain, in the brain of people who've died of Alzheimer's disease when they come to autopsy, is you see this sort of, you know, pattern of this pathology, the tangle pathology distributed in discreet regions of the brain...

FLATOW: Right.

DUFF: ...like region A, B and C. And they're not - how they're related, why that's happening is something that we wanted to explore in this mouse model.

FLATOW: So now that you know that the disease is spreading by this protein, I imagine that's exciting, because there might be someway - to find someway to sop up the protein from spreading around.

DUFF: Yeah. That's exactly what we're hoping to be able to do. We are a long way from any sort of development of therapy that could do this. But the idea here is that, yes, you can develop specific biological reagents, such as an antibody against the tau protein that's in these tangles. And as it leaves the cell, an antibody could perhaps intervene, you know, and prevent it from actually being picked up by the neighboring cell and suck it out, and prevent this, what we're calling spread, between brain regions.

FLATOW: Does the protein have to latch on to a receptor on the cell?

DUFF: We don't know anything about the mechanism. We don't know how it gets from one cell to another, and that's an area of very intense research, not only in Alzheimer's disease, but this has actually got parallels in some of the other diseases. Synuclein is another - is a protein that's seen in Parkinson's, and we think it has a mechanism similar to this to get around the brain.

FLATOW: You know, we used to all hear people talking about - and I didn't hear you say this word once yet. We use to all hear of a focus on something called the plaques.

(SOUNDBITE OF LAUGHTER)

FLATOW: Everyone thought the plaques, right, were the reason for the Alzheimer's, and you're saying this is not true anymore.

DUFF: No. We're not saying it's not true. We've just taken the focus of plaques, where it has been, as you say, for many, many years. And we really are not - this isn't a - it's us or them, you know, type of deal where we're really - we've looked at the tau protein because it has this very interesting distribution in the disease as a disease progresses in humans. But we're not - the amyloid plaques are certainly there, and we think they're major parts of the disease. But we believe there's some sort of synergy between these two proteins, and possibly where they are in the brain, that actually gives this full-blown Alzheimer's. So, you know, no, nothing is wrong with amyloid, but we really want to draw attention to this new aspect of the disease.

FLATOW: Here's a tweet that came in from Liz Haneiki(ph), who says: Do you think the way Alzheimer's tangles spread is related to the way prions cause nearby proteins to misfold?

DUFF: That's a very insightful question. And, in fact, we've taken quite a lot of cues from the prion field for actually proposing how we think this is actually being passed on - this pathology is being passed on. What happens in prion is that the abnormal protein binds to and converts the normal protein to its abnormal form and that's called templating. And we believe that's a major component of how this protein is actually getting beyond the original cell in which it is, and really spreading, you know, all over the brain is through some kind of templating on to the normal tau in a cell.

FLATOW: Is there a way, now, then, if you believe this mechanism to be true, if it is malfunctioning, malformed, the tau protein, is this something that could be used in a test to see - or part of a diagnosis of Alzheimer's?

DUFF: Well, we - yes. We need first a biomarkers. You know, we've been trying to develop biomarkers for - that we can test in the CSF of patients and the stage their disease and also imaging biomarkers where we can actually use something like PET imaging to identify these abnormal forms of the protein and where they are. We've been very successful for imaging biomarkers for amyloids, and it's used quite extensively, now. But we really haven't got anything for tau. So, yes, we need these tools. They'll help us with diagnosis and with estimating progression and staging of the disease, and then, you know, efficacy of treatments, if we can actually monitor how well the treatments have attacked these proteins.

FLATOW: Has anybody started work on the treatments, or possible testing of treatments for this?

DUFF: Not for this, no. And I think we're a long way off. This particular mechanism is really pretty new even though it's been explored, as a I said, in other diseases and in other models, not just ours. But this - it's really opening up a new window of opportunity, I think, for developing drugs. But, no, we're a long way from any therapeutics coming down the line on this.

FLATOW: And I said that because there's another group at Harvard that has similar findings, I understand, and done completely different than yours, I mean independently of yours.

DUFF: Right, independently of ours. They actually have - they had the identical idea as to how to model this aspect of Alzheimer's disease in a mouse, and they have a parallel paper, and it's coming out in a couple of weeks. And that's actually very gratifying for us because this is a, you know, this is a - in a way, we were nervous about this whole mechanism being correct - and it's very good to have complementary and reproducible data between two different independent labs.

FLATOW: So you thought you might be out on a limb a little bit.

(SOUNDBITE OF LAUGHTER)

DUFF: Yes, we did think we would be, but I think there's plenty of data, both - there's also work that has gone on by several other groups around the country, you know, that's preceded this, that's led up to this being a pretty robust idea.

FLATOW: Well, let's say that your idea is true and it pans out, how would you explain why this shows up in older people?

DUFF: Well, you know, we don't - aging is a major component of risk for getting the disease and for the disease worsening. We don't know what initiates Alzheimer's disease, unless that's in patients who have what we call familial Alzheimer's disease, where there's an obvious genetic problem that's causing the disease. We still don't know what the problem is with aging. It's likely to be, you know, the fact that the aging brain is just not as efficient at dealing with process - you know, normal cellular processes. And so it accumulates things that have not been, you know, taken out as garbage as well. You know, we don't know what it is. There's something about the aging brain that's basically in decline and not as efficient as it used to be.

FLATOW: So what's the logical next step? Where do you go from here?

DUFF: Well, we're pursuing the biology of this, intensely now, to understand it better. We're trying to think of therapeutics that we can test in a mouse model. That's the utility and the beauty of having a model of the disease. And, you know, we're trying to really sort of identify better, you know, what the vulnerability is in the different areas of the brain for why they actually develop this and allow this process of spreading to occur.

FLATOW: I guess you're hoping other people join in.

DUFF: We certainly are. We have a very powerful team here. My co-author, Scott Small, is - he's been very instrumental in this work. And, yes, we have a great team, and we have global collaborators working on this with us too.

FLATOW: Well, we wish you the best of luck, Dr. Duff.

DUFF: Thank you very much.

FLATOW: Karen Duff is professor in the department of pathology and cell biology at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and that's part of Columbia University's Medical Center here in New York. I'm Ira Flatow. This is SCIENCE FRIDAY from NPR. Transcript provided by NPR, Copyright NPR.

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