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Published: May 19, 2015, 5:27 p.m.

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Hello, and welcome to Episode Forty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I\u2019m your host, Dan Keller.

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This week\u2019s podcast features an interview with Dr. Lawrence Steinman, who discusses a surprising result involving amyloid, a molecule typically associated with destruction in Alzheimer\u2019s disease, in an animal model of MS.

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Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 1 new trial and 16 other pieces of information. The drugs with important additions are dimethyl fumarate, daclizumab, glatiramer acetate, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.

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According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see last week\u2019s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors\u2019 Pick. It\u2019s a meta-analysis of epidemiological studies of neuromyelitis optica, also called NMO or Devic\u2019s disease. The conclusion of the meta-analysis is that there\u2019s a high level of heterogeneity among the 9 studies that met the inclusion criteria. The prevalence of NMO in the studies ranged from 0.51 per hundred thousand in Cuba to 4.4 per hundred thousand in southern Denmark.

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Will you be attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis next week? If so, please come visit us at the Accelerated Cure Project\u2019s booth. We\u2019ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You\u2019ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.

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Now to the interview. I spoke with Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who has a new twist on amyloid, this time in MS.

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Interviewer \u2013 Dan Keller

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Dr. Steinman, you have proposed that amyloid can be a protective molecule as well as what\u2019s commonly viewed as a destructive molecule. How did you come upon this?

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Interviewee \u2013 Lawrence Steinman

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We came about it serendipitously or by accident. I had a graduate student and I thought I would give that student some low-hanging fruit, and the low-hanging fruit was to take the conventional animal model that we use for multiple sclerosis called experimental autoimmune encephalomyelitis \u2013 EAE. And when she put in these long peptides from an infamous protein named amyloid beta \u2013 A-beta \u2013 she put it into the animals with EAE at the time they were paralyzed, and I thought well, these are molecules that cause even more inflammation in the central nervous system, so they should make the disease worse, or perhaps they\u2019ll have no effect and then we\u2019ll have to think of another project for her PhD. So the student, Jacqueline Grant, came back and said, \u201cWell, I gave the A-beta peptides and the animals are all better, they\u2019re walking around.\u201d And I first reacted, no, you must have confused the cages, let\u2019s do it again. And when we did it again there was the same result, so then we were off to the races.

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There was a second reason besides the low-hanging fruit description. May Han, my colleague, and I had reported the proteomics of MS lesions; so we took well-defined MS lesions, May cut frozen sections and then removed the lesion area with a laser tool, and then we trypsinized, fragmented the proteins, and used a modern technique, mass spectroscopy, to get the proteome, a list of all the proteins in the lesions. So amyloid proteins such as amyloid precursor protein and cal protein are found in the lesions themselves, so I thought that that was a second opportunity, a second foundation for doing these experiments in EAE; let\u2019s see what happens when we augment, if you will, a naturally occurring protein found in the lesion to see perhaps what it\u2019s doing. But, again, my bias, based on the dominant theory in Alzheimer\u2019s disease is that amyloid was going to cause harm in MS as well as Alzheimer\u2019s.

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MSDF

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In these experiments, the amyloid was injected IV so it seems to circulate, but does it get to the brain in these mouse EAE models?

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Dr. Steinman

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Actually, it does not get to the brain. We\u2019ve actually put it into the brain directly to see if it would spread throughout the brain, and in our hands the molecules we\u2019re working with do not spread. Most of these experiments showing a prion-like spread of amyloid is done in animals that are overexpressing the amyloid proteins in the brain so that they\u2019re sort of tilting the balance to enhance spread if it\u2019s going to occur, but we don\u2019t get these amyloid molecules into the brain when we inject them intravenously, nor do we spread them around when we injected them directly into the brain.

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MSDF

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So if you\u2019re injecting them peripherally, do you think that there is some direct effect, or do you think they\u2019re acting through lymphocytes or other circulating cells?

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Dr. Steinman

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Well, we now know that there are at least two mechanisms. One is that when we are injecting them peripherally, these amyloid-like molecules, they go to sites of inflammation and this could include sites of inflammation within the brain. But remember, they\u2019re on the vascular side of the lesion. And they act in a way like molecular sponges. The amyloid molecule is very sticky; in fact, when you try to work with some of the amyloid molecules, they\u2019re like bricks, they stick to the walls of test tubes, and more importantly, they stick to each other and form these long, brick-like fibrils.

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So what they\u2019re doing when we put them into the circulation is they\u2019re sopping up many of the inflammatory mediators that appear in the circulation during inflammatory diseases, including inflammatory diseases of the brain. These inflammatory mediators include the complement proteins and some of the famous apolipoproteins that we\u2019ve heard about in reference to Alzheimer\u2019s, we\u2019ve heard the most about apolipoprotein E. So these amyloid molecules, when they\u2019re in the circulation, actually stick and take away, precipitate away these inflammatory mediators. So I call it a molecular sponge.

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There\u2019s another set of mechanisms that we\u2019re learning about that we\u2019re able to use these amyloid proteins to do a couple of things to lymphocytes. One, it sets up a type 1 interferon response in lymphocytes. So the amyloid fibrils are a known trigger for the production of type 1 interferon, and type 1 interferon is actually beneficial for neuroinflammation; we have approved drugs. It\u2019s doing another thing that we\u2019re on the verge of publishing, but I\u2019ll sort of give the headline without too many details; it\u2019s setting up a type of lymphocyte that has a more regulatory function. So these are all rather unexpected roles for amyloid proteins.

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MSDF

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And you have done adoptive transfer of some of these lymphocytes and find similar effects?

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Dr. Steinman

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Yes. And the adoptive transfer experiments are very interesting. When we set up the system to produce a lot of type 1 interferon after we give an amyloid fibril, if the type of disease is what\u2019s called the Th17 disease, the increased beta interferon actually worsens that, and if we create a disease that is called T-helper 1 \u2013 Th1 \u2013 then the type 1 interferon is beneficial. So we\u2019ve engineered some amyloid structures so that they trigger less type 1 interferon, and when they trigger less type 1 interferon, then they work in both the Th1 and Th17 models. We published on that in the Journal of Experimental Medicine. But, again, even here with the type 1 interferon, the effect is nuanced and we can engineer these amyloid structures to be really beneficial and to take away the harm.

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I wanted to say one thing, that clinicians and working scientists generally understand amyloid very well. Amyloid-beta that\u2019s well known. Other amyloid proteins that people are, of course, familiar with are tau, prion protein, alpha-synuclein. But an amyloid structure is a general description of a protein that forms beta sheet, so the beta strand structure allows through hydrogen bonds the formation of what you should think of as a venetian blind, these monotonously parallel sheets that actually intercalate dyes, like Congo red or thioflavin T, so that when you shine polarized light on them they refract it in a polarized way. So we can make these structures, if you will, they\u2019re organized nano particulars, to be more or less water-soluble, to be greater or lesser inducers of type 1 interferon. So there\u2019s a whole armamentarium of very interesting amyloid structures that we can engineer to provide benefit in different situations.

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Now what does this all mean for the Alzheimer\u2019s hypothesis? And we\u2019re doing an audio interview, so I\u2019m sort of smiling wryly. I don\u2019t want to get into that because we haven\u2019t done the experiment in the amyloid-beta overproducing transgenic mice that have served as the model system to test whether various amyloid-lowering procedures will provide benefit, we just haven\u2019t done that. And we\u2019ve tried our particular approach in a number of other conditions ranging from stroke to EAE, as I said, to experimental heart attacks. And in the systems that we\u2019ve studied, we see benefit.

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MSDF

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But as a further proof of concept of what you have found in the protective effect of amyloid, you\u2019ve looked at amyloid precursor protein knockout mice. Is that right?

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Dr. Steinman

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Yes. Well, that\u2019s a whole interesting story, and thanks for reminding me. So in a series of experiments that we have done and others have done, we first noticed that amyloid precursor protein knockout mice, they had worse EAE. Another person in Australia, Colin Masters, who\u2019s actually one of the leaders in the field of Alzheimer\u2019s research, looked at experimental head trauma, and in the amyloid precursor protein knockout mouse, they had a worse condition after head trauma that was alleviated by giving amyloid precursor protein in its soluble form. And then other people have shown that experimental encephalomyelitis is worse in prion knockout animals and in tau knockout animals.

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We had been working with a protein called alpha-B crystallin, which is also an amyloid-forming protein, and we noticed that EAE was worse in the absence of alpha-B crystallin. So there\u2019s a long series of experiments that loss of function, loss of the parent protein of these amyloid-producing molecules, leads to worsened inflammation, whether it\u2019s EAE, head trauma, or somebody else did it in experimental heart attack. And we also did it in experimental stroke, so under a variety of conditions.

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So this makes the argument even stronger, suggesting that amyloid structures when augmented can provide benefit and reduce inflammation, and when absent can actually exacerbate inflammation; so gain of function better, loss of function worse. So you have to look at the amyloid molecule as something that is not always harmful and pathologic. Whether it is the main culprit in Alzheimer\u2019s, whether Alzheimer\u2019s is an example of neuroinflammation, I leave it to people in that field because I really don\u2019t want to take them on headlong at this point in time when we have all these fascinating results elsewhere. But I let the listeners draw their own conclusion based on the published work that I\u2019m talking about, not only from my own lab but from other investigators all over the world.

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One might want to think a little bit differently the next time one thinks about the deleterious effects of amyloid in Alzheimer\u2019s, but I\u2019m not going to be the one that takes on that massive scientific opinion, we\u2019ll just have to see how it works out. I hope everyone\u2019s been right over all these years because we certainly need some answers in that field. And if they are right, then we\u2019ll have to integrate the kinds of things that we\u2019re understanding about the role of amyloid proteins in other types of inflammatory conditions with a positive result in Alzheimer\u2019s when it\u2019s taken into the clinic. If it turns out that the experiments do not succeed in Alzheimer\u2019s, then it will be easier to reconcile these different outcomes. But I think we\u2019ll have to be patient; science doesn\u2019t move as fast as some of us would like to have it move.

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MSDF

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What was the time course of seeing a result by injecting the amyloid in your EAE models?

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Dr. Steinman

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It\u2019s very fast. When you inject the amyloid, it\u2019s within 48 hours. If you stop giving the amyloid \u2013 we like to give it every day \u2013 if you stop giving it for a few days, the inflammation recurs, and that suggests that these amyloid structures are acting like a pharmaceutical. It\u2019s not one of these situations that you sometimes see in science; you give the molecule once or twice and the disease goes away forever. This seems to be suppressing ongoing inflammation while it circulates, and when you take it away the effect is gone and the disease recurs, so that\u2019s very interesting.

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MSDF

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The effect seems to be too quick for remyelination to be occurring as the answer, but when you give it chronically do you see remyelination?

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Dr. Steinman

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So far, we haven\u2019t looked for long enough periods of time or with sensitive enough techniques. Your question triggers an experiment and we should really take a look at that. I would imagine that if you can abrogate inflammation that you\u2019ll allow for remyelination if there\u2019s anything left in the oligodendrocyte precursor to remyelinate itself, or if you need a little augmentation, it would be good to do a stem cell type of therapy under the protection of this kind of antiinflammatory approach.

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MSDF

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Are you planning any early human trials?

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Dr. Steinman

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Ha! I chuckle because this is a tough one to bring into the clinic. I\u2019ve been funded by people who first scolded me for saying don\u2019t take this too fast into the clinic, because I like to translate results. In this one, we\u2019ll have to be more cautious than we might for other types of therapies.

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MSDF

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Is there anything important to add?

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Dr. Steinman

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I thought the questions were very comprehensive. And as you can see from where our matters stand now, there\u2019s a lot of positive leads to pursue. And I think we\u2019ll have to be cautious about translating in the fields of multiple sclerosis or stroke because of the infamy of the molecule I\u2019m working with, but we\u2019ll get there. Thank you.

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MSDF

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Thank you.

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Thank you for listening to Episode Forty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF\u2019s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.

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Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.

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We\u2019re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.

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