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Fri February 10, 2012
Drug Rapidly Counters Effects of Alzheimer's In Mice
Originally published on Fri February 10, 2012 1:58 pm
JOHN DANKOSKY, HOST:
This is SCIENCE FRIDAY. I'm John Dankosky, sitting in for Ira Flatow. Scientists have long been studied amyloid beta, those sticky protein fragments that build up in the brains of Alzheimer's patients. What you may not know is that amyloid beta is produced in everyone's brain, including my brain as I speak to you right now.
The difference is people who get Alzheimer's later in life are unable to clear this protein from their brains. So over time, it accumulates and can damage brain cells critical for memory and thinking. Now scientists say they may have found a way to boost the body's natural ability to clear amyloid beta from the brain.
In a study in Science, researchers say they gave mice with Alzheimer's symptoms an FDA-approved drug, and within a few hours, they began to see dramatic results. Dr. Gary Landreth is a professor of neurosciences and director of the Alzheimer Research Laboratory, Case Western Reserve University. He's co-author of the study in Science. He joins us today from WCPN in Cleveland, Ohio. Welcome to SCIENCE FRIDAY.
GARY LANDRETH: Thank you, I'm glad to be here.
DANKOSKY: If you have a question about this Alzheimer's study, you can give us a call. Our number is 1-800-989-8255. That's 1-800-989-TALK. If you're on Twitter, you can tweet us @scifri. If you want more information about what we'll be talking about this hour, go to our website, www.sciencefriday.com, where you'll find links to this topic.
So first of all, Dr. Landreth, explain the difference between amyloids, a soluble amyloid, amyloid plaques. What do we know about their effect on the human brain?
LANDRETH: OK, so as you're listening to me, as a consequence of normal brain activity, you're generating amyloid, which is a small, rather sticky peptide that's generated at the synapse. And what it does is, over time it accumulates in the brain, and this is what underlies the learning and memory losses that are associated with Alzheimer's disease.
Now, most of us, through most of our lives, are able to effectively clear this little peptide from the brain, but over time, due to sort of age-related inefficiencies that accompanies normal aging in many cases, this peptide slowly accumulates, and it sort of poisons the capacity of nerve cells to communicate with one another.
And this is what sub serves the memory losses. Now as the disease progresses, these small, sticky peptides stick to one another, and they form fibrils, and then they form plaques, which sort of typify the path - they are the pathological hallmarks for the disease.
DANKOSKY: So now I wanted you to talk about this gene that we're going to be talking about here, a polyprotein-E gene. Explain exactly what this is. What do you know about this gene and how it behaves in the body?
LANDRETH: So this is the apolipoprotein-E gene, and it is the vehicle through which cholesterol and (unintelligible), that is the lipids in the brain, are trafficked around. And an analogous situation goes on in the periphery. So our contribution to this discussion was, a few years ago, we recognized that apolipoprotein-E was part of what you could think of as a garbage disposal system whereby these amyloid peptides are then degraded.
So they're cut up into smaller bits and basically gotten rid of. And this is the normal biology of the brain, where apolipoprotein facilitates the normal physiologic clearance of these amyloid peptides.
So we reasoned that since we know that Alzheimer's disease is associated with accumulation of amyloid peptides in the brain, if we had increased the capacity of the clearance system, that is the garbage, the capacity of the garbage disposal, that should facilitate recovery of memory.
And so we actually knew how to do that because we knew something about the genes that regulate apolipoprotein expression, and we chose a drug which would affect apoli-expression.
DANKOSKY: And what is this drug, and what is it supposed to be used for?
LANDRETH: Well, so what we figured out, and we've been working on this question for about a decade, so this is well-known terrain to us, that we selected a drug which activates a receptor called retinoid X receptors - RXR. And as we cast about for a drug that would stimulate this receptor, we came upon an FDA-approved drug called Bexarotene.
And it is remarkably effective in stimulating apoli-expression. Now this drug has been approved by the Food and Drug Administration for the use in cutaneous T-cell lymphoma, this is a skin cancer...
DANKOSKY: Yeah, you were about to say it's not a very good drug. Does it work for skin cancer patients?
LANDRETH: So it's actually uncommonly prescribed. There are only about 2,000 prescriptions in the United States every year. And it's not particularly effective in T-cell lymphoma. It's a second- or third-line drug. And actually, its actions in cancer are unrelated to the way we're using this drugs, and its actions in cancer cells are not particularly relevant.
DANKOSKY: So you believe that this drug is going to work in the way, essentially stimulate this particular gene. How did you test it? How did you go about finding out that this actually works?
LANDRETH: Well, so I have a fantastic collaborator, John Cirrito at Washington University, St. Louis, and so what John did was he put a microdialysis into the brain of an Alzheimer's mouse. And what this allows us to do is to sample the fluid between the cells and so we can measure how much amyloid is circulating in the brain at any given moment in time.
And so John did a rather remarkable study whereby he was able to give this drug, and we were able to see within six hours that the levels of amyloid in the brain fell about 30 percent.
And more importantly, one dose of the drug would suppress amyloid levels for as long as three days. And I think this is an unprecedented observation, which suggests that we might have a therapeutic that's maybe of use in certainly animal models of the disease.
DANKOSKY: If you want to join our conversation, 1-800-989-8255, that's 1-800-989-TALK. I want to go to a phone call here. Greg(ph) is in Boise, Ohio. Go ahead, Greg, you're on SCIENCE FRIDAY.
GREG: (Unintelligible). I wanted - it's Boise, Idaho. And I wanted to ask if he could go into a little bit more depth as to these plaques. You said that they were produced, but what mechanism is actually making them? You know, if this is something that the brain needs to make for some reason, or is it a byproduct of the other process? And, you know, so that we can better understand why these plaques are being made rather than just that they're being made.
DANKOSKY: Thank you, Greg.
LANDRETH: Oh, certainly. OK, so as you accumulate, in the Alzheimer brain, these amyloid peptides, these are rather sticky proteins, and they stick to one another, they form fibrils, and eventually the form plaques, which are, you know, these characteristic feature of the disease.
Now, one of the other bits in this story is that if we looked at mice, at Alzheimer's mice, with extensive plaque deposition within their brains, what we observed was that the plaques were removed. We lost about 50 percent of the plaques within 72 hours.
And frankly, no one had ever seen anything of this speed or magnitude before in these mouse models. So that's - so the idea is, or has been, that the plaques are really bad things, and they were sort of the bad actors in the disease.
Now that view has evolved over the last few years, and so there's an active an vigorous controversy over whether the plaques are really sinks into which capture all the bad forms of amyloid, or are they reservoirs, which continually release toxic forms of amyloid back into the brain.
And that controversy is ongoing. I think one of the surprising things about our study was that we were able to remove them, and this occurs through the action of a housekeeping cell in the brain called a microglia, who see these things as foreign material. And we were able to stimulate the (unintelligible), basically cells ate the amyloid plaques.
DANKOSKY: Before we run too low on time, I want to ask you to maybe explain how these mice behaved differently. You know, what sorts of behaviors were they experiencing before, and what happened when you gave them this drug over the course of hours?
LANDRETH: Oh, certainly. So, you know, the truth is that the most important, and maybe the only important output of this study, was do the mice get smarter, do they regain their capacity to learn and remember. So we used three different animal models of Alzheimer's disease, and we used five different behavioral tasks, which interrogate different aspects of memory in different parts of the brain.
And in each case, within three to seven days, we could completely reverse the behavioral deficits which these mice exhibit. And I think this is particularly exciting because what this suggests, at the early stages of Alzheimer's disease, that we can reverse the cognitive memory deficits.
DANKOSKY: Yeah, the early stages, and they're mice. So mice aren't people. How are they different, and what should we extrapolate from the fact that this works with mice?
LANDRETH: OK, so our mice models are simply models of the disease, they are not the disease. And what they do is really, sort of, model the earliest phases of the disease, the mice do not lose their neurons, and we actually don't understand that. Suffice it to say that they're incomplete, and I think you have to, you know, take this work with a grain of salt because the - these are models of amyloid doses and I think while the results are really quite provocative, we have to be clear that these are mice, and that's - these are rather contrived sorts of tasks we're asking them to do.
DANKOSKY: So how long - I mean, that's something a lot of people are going to be asking is how long will it be until this can be something that works in humans? And since this is an FDA-approved drug, I mean, can I just go get some myself and try this out?
LANDRETH: OK, so let me tell you what we're doing right now. At the moment, we do not know how to optimally deliver this drug to a mouse, much less a human, and I can tell you that the doses that were published in the study in Science are much too high, and we can work with much lower doses, and we don't know exactly what that is, but we're working on it.
So we need to establish how to deliver this to mice. The other thing is we don't know that this works in humans at all. So the first clinical test, which we will get underway in the next month or so, is to ascertain whether the human brain responds to this drug like the mice do. And until we ascertain that, you know, we can't go forward, and that's a necessary prerequisite for any subsequent development. The other thing is...
DANKOSKY: Quickly, yeah.
LANDRETH: I want to say loudly and clearly is don't try this at home. This is an FDA-approved drug, which you can in principle get a prescription and go down and buy at your pharmacy. I would point out to you this is not a great idea. We have no idea what the effect of this drug will be in humans with Alzheimer's disease.
Now, I'll tell you that our clinical experience in trials with other types or drugs suggest that pulling amyloid out of the brain has possibly negative consequences.
DANKOSKY: And we will have to leave it there, but I'm glad we got this cautionary tale in at the end. Dr. Gary Landreth is a professor of neurosciences at Case Western Reserve University. Thank you very much for joining us.
After the break, the risks and rewards of yoga. Stay with us.
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DANKOSKY: This is SCIENCE FRIDAY from NPR. Transcript provided by NPR, Copyright NPR.