Alzheimer's Potential Missing Link

Reporting in Neuron, researchers write that a protein called mGlu5 may play a role in nerve cell death in Alzheimer's disease. They found that blocking the protein with an existing drug restored memory in mice. Lead author Stephen Strittmatter discusses what this means for future Alzheimer's treatments.

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IRA FLATOW, HOST:

This is SCIENCE FRIDAY. I'm Ira Flatow. This is Alzheimer's Awareness Month, in case you didn't know that. Dr. Alois Alzheimer first described a type of dementia that could go on to - that would go on to bear his name - first described that in 1901. Now over a century later, more than five million people in the U.S. are living with Alzheimer's, according to the Alzheimer's Association, and we still are looking for the exact cause and treatment for the disease.

Researchers writing in the journal Neuron say they have found a potential missing link - at least in mice - that may give insight into how Alzheimer's Disease causes these neurons to die. Stephen Strittmatter is Vincent Coates Professor of Neurology at Yale University's School of Medicine in New Haven, a senior author on that paper. He's cofounder of Axerion Therapeutics, which is working to develop therapeutics for Alzheimer's Disease. Welcome to SCIENCE FRIDAY.

STEPHEN STRITTMATTER: My pleasure to be with you.

FLATOW: Now, correct me if I'm wrong here. Now, Alzheimer's is a step-by-step process. You discovered, at least in lab mice, a way of blocking the destructive pathway that kills brain cells, and you've actually achieved restoring memory; is that correct?

STRITTMATTER: That's correct. In these studies, the laboratory mice develop part of human's Alzheimer's Disease. They certainly have a progressive process that accumulates amyloid in the brain. And they develop memory deficits and lose synapses. And we developed a process whereby we could reverse the synapse loss and the memory deficit.

FLATOW: By doing what? What was the process?

STRITTMATTER: Right. So this involved some degree of detective work to try to uncover the mechanisms and then to interrupt those mechanisms. So what had been known for a while, really going back almost the full hundred years, is that this amyloid plaques develop in the brain of Alzheimer's patients. Moreover, they're composed of a particular peptide, Amyloid Beta. And it's not the plaque itself most likely, but oligomeric states, abnormally folded parts of the protein which attack neurons and make the neurons sick.

And that's why patients with Alzheimer's Disease have memory deficits. So what we've focused on here is how these amyloid oligomers interact with the neuron and then make the neuron lose its synaptic function and have memory deficits. So in this process we knew a few things beforehand. We knew that this particular misfolded form of amyloid, Beta Peptide, the oligomer, would interact with prion protein on the cell's surface.

This is on the outside of the neuron. And we knew inside the neuron that this would trigger by chemical events, including kinases, enzymes being activated, that changed synapses. What we didn't know was how the outside of the cell interacts, talks to, signals to, the inside of the neuron. And that's what this new discovery is about, that the length between those two is a particular protein that crosses the cell membrane of the neuron called mGlur5 or Metabotropic Glutamate Receptor Five.

FLATOW: And so if you block the transmission of this protein through the cell, you stop the death of the neuron. Is that correct?

STRITTMATTER: Well, in the mouse models we don't have a lot of cell death but we do have loss of synapses. So the whole neuron in the mouse models doesn't die.

FLATOW: Right.

STRITTMATTER: But its business end, the synapse where it talks to other neurons and creates the network that allows mice and humans to think...

FLATOW: Right.

STRITTMATTER: ...this synapse connection is lost. So that's probably the earliest stage of neuronal damage. In fact, synapse loss in human Alzheimer's patients is more severe than actual cell death. So what we're really studying in the mice is the loss of synapses, not the loss of cells.

FLATOW: So you could prevent the loss of the cells by counteracting this process?

STRITTMATTER: That's right. If we used a drug that can block - the drug is called MTEP. If it blocks the mGlur5, this link between the outside and the inside of the neuron, then memory deficits in the mice and synapse loss in the mice were reversed. They recovered back to the performance of wild type mice.

FLATOW: And how common is this substance, this drug? Can you, you know - do you have to make it, improve it, or is it around?

STRITTMATTER: Right. Well, let me step back. The link, this protein that is the link between the outside and the inside, is present in all of us. So it's not only in Alzheimer's Disease. But it's being abnormally triggered by the amyloid beta prion protein pathway. So how can we target that with drugs? We used a drug which is known to exist in previous studies to block this pathway.

But we had to do so very gingerly. If you use too much of this drug, it prevents the normal functioning of the mGlur5 protein, and that has a role in normal synaptic transmission in the brain. If you use too much of the drug, it actually shuts down this process. So there's a narrow dose window in the studies that we used.

Our hope for the future, what we think will be possible, is to look at this and develop one that will block selectively the amyloid prion interaction with mGlur5 but preserve the normal glutamate reception that is the physiologic role of this protein.

FLATOW: So you have to be very - it's not just a question of carefully adjusting the dosage. You're looking for something else.

STRITTMATTER: Well, I think that would be one approach...

FLATOW: Yeah.

STRITTMATTER: ...to very carefully adjust the dose. And we can do that in controlled mouse studies where all the animals have the exact same genetic background and all the mice are in our laboratory where we can adjust the dose. In the real life clinical situation, the idea of hitting that very narrow dose window may create a real challenge across the entire spectrum of Alzheimer's Disease, where the disease progresses over time.

FLATOW: You know, we're seeing so many different studies coming out about Alzheimer's now. I mean some that can clear plaque, some that interfere with the transmission between cells - between the cell wall like yours. Why? What's happening in the world of Alzheimer's research? Is there just a lot of money floating into it now? Or are we making real progress?

STRITTMATTER: Well, I think we are making progress in our understanding. I think there's an enormous appreciation amongst the medical and scientific community how important Alzheimer's is. Is the money flowing in? I think this research, in large part, is getting done despite moderate changes in the amount of funding. I think it's still an area of research where the medical need far, far, far outstrips the amount of investment from government sources or from pharmaceutical industry in actually developing a cure.

FLATOW: Mm-hmm. The fact that the mice in your study were actually able to recover their memory after the drug was administered is very hopeful. I mean we usually think about - well, the brain cells are destroyed and they're never coming back.

STRITTMATTER: Well, I think we don't know exactly how the mouse model will translate to human.

FLATOW: Mm-hmm.

STRITTMATTER: I think that remains an open question. I would say, as I was emphasizing earlier, in these mouse models there is amyloid pathology, and synapses are lost, but the whole brain doesn't shrivel. There isn't cell death. So it probably mimics very early stages of the Alzheimer's process, what has been labeled mild cognitive impairment.

FLATOW: Mm-hmm.

STRITTMATTER: And may not model the late stages of Alzheimer's when a lot of cells have died. That may not be reversible. We wouldn't expect it would be reversible with this type of intervention. So in late disease it may reverse a portion of the deficit but halt the disease process rather than reversing all of it.

FLATOW: Is the kind - is the successful treatment you used on the mice, is that toxic to humans? Toxic to the mice? Or is it a commonly available non-toxic drug?

STRITTMATTER: Targeting this pathway has entered clinical trials. Not for Alzheimer's Disease but for Fragile X Syndrome, drugs targeting this same molecule. So again, there is a therapeutic window. If the disease is very severe, the consequences are bad, then even these non-selective blockers, as we used in this study, may be beneficial. That's how they're being used in Fragile X Syndrome.

For Alzheimer's Disease, as I was saying earlier, I think finding one that selectively blocks the amyloid prion protein interaction may be a much better approach, one that doesn't require this very precise dosage titration.

FLATOW: Could you not find in this test of the Fragile X Syndrome some people suddenly showing, the people in the test, better memory and not as rapid loss of memory as not - not something they were testing for but you might discover it that way.

STRITTMATTER: Well, part of that syndrome does include cognitive abnormality. So that's part of the aim in those studies. Of course the mechanism is completely different.

FLATOW: Right. But that's what I'm talking about. You know, maybe these people are - some of them may be pre-Alzheimer's. I'm just guessing here how that might, that study might show up. You might see unexpected consequences, you know, that might be positive.

STRITTMATTER: Yeah. Most of those - I don't know all the details of the study but the majority of those individuals would be in the pediatric age group. So I doubt that that particular study will be especially informative with regard to Alzheimer's Disease.

FLATOW: Mm-hmm. So you...

STRITTMATTER: At least in the near-term.

FLATOW: So you say there are clinical studies that might be coming up using your discovery?

STRITTMATTER: Well, I think that's not - there's not one that's been started. I think my own feeling is that it would be preferable to try to develop a variant on the drugs we're using today, one that has a more selectivity between the Alzheimer's pathway and the normal physiologic function of mGlur5. So I would suggest that probably some more drug discovery work would be preferable to moving ahead into the clinic with the existing drugs.

FLATOW: And are you headed...

STRITTMATTER: But it's, you know, I guess...

FLATOW: Yeah. Are you headed in that direction? Or is somebody headed in that direction?

STRITTMATTER: That's right. That's something we're very interested in doing, in identifying compounds that target this particular molecule, this protein mGlur5.

FLATOW: Mm-hmm.

STRITTMATTER: And there's certainly been - there's many compounds that have been discovered that target it; we just need to ferret out the ones that would be most beneficial for Alzheimer's without having...

FLATOW: Right.

STRITTMATTER: ...disruptive effects on normal physiology. That's a relatively simple task.

FLATOW: Yeah. Dr. Strittmatter, thank you for taking time to be with us today.

STRITTMATTER: It was my pleasure to talk to you. Thank you.

FLATOW: You're welcome. Stephen Strittmatter is Vincent Coates Professor of Neurology at Yale University School of Medicine. And he's also cofounder of Axerion Therapeutics which is working to develop therapeutics for Alzheimer's Disease. I'm Ira Flatow. This is SCIENCE FRIDAY from NPR.

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