Could Brain Infection Set the Stage for Alzheimer’s?
One of the hallmarks of Alzheimer’s disease is the buildup of the protein amyloid-beta in the brain. But amyloid-beta isn’t just limited to humans. It’s found in three-quarters of vertebrates. Even the coelacanth, a 400-million-year-old fish, shares amyloid-beta genes with humans.
That remarkable preservation across evolutionary time, and the protein’s resemblance to other antimicrobial compounds in the body, led neurobiologist Rob Moir to wonder about the function of amyloid-beta. Surely it couldn’t just be junk, gumming up the brain?
Indeed, a few years back, Moir teamed up with neurologist Rudy Tanzi and others to show that amyloid-beta itself has antimicrobial properties. And now, reporting in Science Translational Medicine, they write that the protein acts as a foot-soldier against fungal and bacterial infection in vitro, and in the brains of nematodes and mice. Within just 48 hours of infection, they saw clumps of amyloid appear in the hippocampi of mice—and trapped in the center of each glob, the invading microbe.
The new findings, they say, suggest that infection may spur the buildup of amyloid-beta—and that Alzheimer’s disease could be a toxic side effect. Their theory is provocative, and will probably get a great deal of pushback, says Moir. “We’re basically saying 30 years of assumption are wrong, and that’s not gonna go down great.”
Rob Moir is a neurobiologist at Massachusetts General Hospital and an assistant professor at Harvard Medical School in Charlestown, Massachusetts.
Rudy Tanzi is a professor of neurology at Harvard Medical School and is vice-chair, neurology at Massachusetts General Hospital in Charlestown, Massachusetts.
IRA FLATOW: This is Science Friday. I’m Ira Flatow. One of the hallmark symptoms of Alzheimer’s disease is the plaque that piles up in the brain, the plaque that contains the protein amyloid beta. And for years, amyloid beta has been cast as a villain, the toxic junk that gums up the brain.
But it turns out it’s possible the protein may actually be trying to help us. Because a new study out this week claims that amyloid beta may actually be a sort of a foot soldier in the immune system that traps and ensnares any bacteria or fungi that dare to invade the brain. He keeps them from doing more damage.
But the side effect of this protection? Over time, as the protein builds up in response to those infectious insults, dementia maybe the toxic side effect. That’s the provocative theory, sure to kick off a lot of discussion in the Alzheimer’s community that my next guest published this week in the journal, Science Translational Medicine. And it’s been a long road to get there.
Rob Moyer is a neurobiologist at Mass General Hospital, Assistant Professor at Harvard Med School. Welcome to Science Friday.
ROB: Thank you. I listen to your show all the time. Glad to be here.
IRA FLATOW: Thank you. Rudy Tanzi is a Professor of Neurology at Harvard Med School, and Vice Chair of Neurology at Mass General. Welcome to the program.
RUDY TANZI: Thanks very much. It’s a pleasure.
IRA FLATOW: Dr. Moyer, from what I understand, it was a struggle to get this paper published. Rejected six times without review?
ROB: Yeah, you could say the headwinds were a hurricane force, I would say. but it has made it through. And the reception generally, actually, has being surprisingly positive. So we’re very pleased about that.
IRA FLATOW: And legend has it that you had your inspiration for this project one night at a bar.
ROB: Uh, yes.
IRA FLATOW: [LAUGHING] Come on, fess up. You can fess up. No one’s listening. Just you and me.
ROB: Well, it wasn’t a bar so much. It was every Friday, we have an attitude adjustment, or readjustment hour.
IRA FLATOW: That’s what I meant, actually.
ROB: Yeah, at the department. And I did indeed take a couple of Corona’s, and came across a peptide called LL37, and it struck me that these were very similar to a beta. Whether that would have happened without the Corona’s, I’m not sure. But anyway– [LAUGHING]
IRA FLATOW: Inspiration.
ROB: It’s history now.
IRA FLATOW: Dr. Tanzi, tell us what happens exactly when the amyloid beta sees an invader. Walk us through the process you observed in the paper.
RUDY TANZI: Well, in this case, whether it’s a bacteria or fungus as you said, or even a virus, the small protein that makes up the plaque, called a beta, will start to clump up. And you need these clumps for it to work. And it’s these clumps that are also toxic to nerve cells.
And these clumps we call oligomers bind to the microbe, and actually prevent it from binding to a cell, like a neuron. So, first, it prevents the adhesion. And then, it actually, we say it glutamates. That means it clumps up the bacteria and viruses into a big ball, kind of like when you’re sweeping the floor and get everything through the dust pan.
And then, it forms a web, a trap, and it entombs so it can’t cause any harm. And eventually, it kills it. So it’s a classic mechanism by which antimicrobial peptides throughout the body do their work to protect us. Except this time, it’s in the brain, and it results in a plaque.
IRA FLATOW: And you get too many of these disease-fighting plaques, and then you get Alzheimer’s.
RUDY TANZI: Yes. So the idea is that– we had a paper a year or so ago, Alzheimer’s in a dish, where we created Alzheimer’s in a Petri dish, a mini brain, so to speak. And there, we could show for the first time when we made plaques from human nerve cells growing in what’s called a brain organoid, that these plaques are sufficient to trigger the rest of the disease. They trigger these things called tangles that kill the nerve cells from inside, and they trigger inflammation.
So that’s the match that lights the fire. But in this case, it’s meant to protect you, but in the end, it turns against you.
IRA FLATOW: So these plaques too are very tough.
ROB: And they have to be, so that the bug won’t crawl its way out. But the problem there is, of course, once it’s formed, it’s very hard for us to clear it as well.
IRA FLATOW: Hm. OK. So you have an interesting theory. You’ve got it working in a Petri dish. What’s the next step? Can you cut open one of these globs of plaque, and look for a microbe inside, and say, see, this is what we’re talking about?
ROB: Yes, we can do that. And in fact, based on this study, we’ve just started what we’re calling a Brain Microbiome Project, with the funding body that actually enabled this work to happen, the Cure Alzheimer’s Foundation. They’ve plunked down half a million bucks, and we are going to look at a whole bunch of brains from Alzheimer’s disease, and ordinary people, and work out exactly what is living in there as you grow older.
IRA FLATOW: I’m sorry. Go ahead. No, you go ahead.
RUDY TANZI: No, I was going to say the Cure Alzheimer’s Fund, based in Boston, is a foundation that funds out of the box projects like this. They funded Alzheimer’s in a Dish. They funded this. And they’ve announced about half a million dollar, the First Brain Microbiome Project.
So the idea would be look at young autopsy brains, aged ones, and Alzheimer’s, and see what’s sneaking in as we get older. You know, our immune system goes downhill, blood brain barrier breaks up. And so, see what’s living inside– not living, but what’s entombed in those plaques. And if we get common culprits from hundreds of brains, then maybe there’s a chance for primary prevention later on against those particular microbes.
IRA FLATOW: Do you have any candidates for which microbes in particular might be most or more responsible?
ROB: There’s actually quite a bit of data out there on this. And the one most closely linked are the herpes viruses. And of course, they’re almost ubiquitous. Herpes I is 90% of people by the time the five-year-old. They’re recurrent chronic infections, subclinical for the most part. So it’s a likely candidate. And it’s popped up very often associated with Alzheimer’s disease.
And this is probably the likely, but not necessarily the only, candidate. One of the things our study shows is the amyloid formation is not dependent on a specific pathogen. It’s a generalized response. It’ll do this whatever you throw at it. That means that it may not be a single pathogen that’s involved in Alzheimer’s disease. It could be a number of them. Spirochetes is a common pathogen.
RUDY TANZI: From Lyme Disease.
ROB: Yeah, Lyme’s disease. And [INAUDIBLE] is also a common infection agent.
RUDY TANZI: Chlamydia.
ROB: Chlamydia as well. And all these things could be triggering this same inflammatory response mediated by a [INAUDIBLE] that leads eventually to neurodegeneration.
IRA FLATOW: Are you saying that if your hypothesis is correct, that you can prove that infection causes Alzheimer’s in the brain?
RUDY TANZI: Well, this isn’t infection the way we normally think about it. It’s not infection that’s causing encephalitis or meningitis. This would be asymptomatic, no clinical symptoms. I mean, in the mouse study, when the bacteria were injected into the mouse brain, and these were Alzheimer’s mice, they were only four weeks old, so they don’t have any plaques yet.
And overnight, they got plaques. But what was most striking to me was that one plaque that’s quite big had one single bacterium in the middle. So you wouldn’t need that much to sneak into the brain to trigger a whole plaque. So to say infection, people think rampant growth of bacteria and viruses.
You just need a few microbes to sneak in and start this process going, and you get a whole plaque with just one of them, at least in the mouse model that you used. Then why don’t know all of us have Alzheimer’s, if it just takes infection by these viruses, or whatever.
Well, after 40, we all have plaques. And those plaques start to cause the tangles and inflammation. It’s just a matter then of your genetics and your lifestyle. And I wrote extensively about this in a couple books, Superbrain and Super Genes, about how lifestyle and genetics combines to determine your response to all of this.
How do you respond to the plaques, and when do you finally succumb to dementia? So that’s where genetics and lifestyle comes in as well.
IRA FLATOW: Could– I’m sorry, go ahead. You wanted to jump in there? Rob?
ROB: Yeah, it really also is probably a dose response effect. And there are some other factors involved, for instance, APOE4 is a risk factor for Alzheimer’s disease. Well, it turns out, it’s also a risk factor for brain infections from a lot of different pathogens, which hitch a ride on it to get into your central nervous system.
So there are a number of things that could be leading to cause the variation that you see in people’s susceptibility to disease.
IRA FLATOW: That you’re doing this Microbiome Project, which sounds really interesting for the brain, could you uncover other diseases, not just in Alzheimer’s, that might also be caused by it? And why should this be the only thing?
ROB: Well that’s true. We may have come across an underlying thing for a number of diseases. There’s about 30 amyloid diseases for people. And that includes some of the big diseases that we have, including diabetes, which is an amylin disease.
Actually, Alzheimer’s is sometimes called diabetes type 3, because the parallels between the two are remarkable, which has been noted for over 50 years. But the underlying basis for that has not been clear. But there’s a peptide called amylin that forms amyloid in the pancreas.
And if it’s doing the same thing that the [INAUDIBLE] is doing, that has some pretty big implications for diabetes as well. And there are others. So yeah–
RUDY TANZI: And Rob, also add that there are known– there are also several known antimicrobial peptides in the body that do cause amyloid diseases in the heart, in the eye, and in the seminal vesicles. So to some extent, for people study into antimicrobial peptides, what we’re seeing in the brain isn’t new to them. What’s new is that it’s defining perhaps how we get the first pathology of Alzheimer’s disease.
ROB: Yeah, the direction of this has been there are antimicrobial peptides that form amyloid diseases. But nobody has suggested that there’s an amyloid protein that is an antimicrobial peptide, until our stuff has come along anyway.
IRA FLATOW: You know, there’s skepticism and the disbelief a little bit about– this reminds me of when people discovered that H. pylori bacteria caused ulcers. I remember that, people saying, you guys are crazy. You know, Barry Marshall actually infected himself with it to prove it, didn’t me?
ROB: He was my old microbiology teacher, as it happens, back at West Australia.
RUDY TANZI: That explains a lot, Rob.
ROB: It does.
IRA FLATOW: I mean, [INAUDIBLE] a motivation. Very seriously, if he was a mentor of yours, does it give you less fear of striking out on your own with an interesting idea?
ROB: Yeah, it does. And his was a cautionary tale. I was among the skeptics. The rumor was at the time– I was an undergraduate, but the rumor was he kept his mice in his garage, because he didn’t have the money to put them in the animal house. And he was certainly considered a wild idea.
But it was. But it proved it also to be correct. So yeah, I think it does kind of give you a little bit of a perspective when you’re close to something like that. So, yeah.
IRA FLATOW: On the other hand, the idea seems to be gathering some of interest, because there was an editorial last month in the Journal of Alzheimer’s Disease by nearly three dozen authors saying, yes, an infection must play a role in a disease, whether it’s herpes, chlamydia, or whatever. And they were saying it’s time, it’s time start the voting. More funding to this infection hypothesis. Why haven’t we been doing this?
RUDY TANZI: Well, I think until now, the evidence was simply, hey, I found there’s some herpes in the brain, or chlamydia. And they didn’t have a model for how that might be causing Alzheimer’s. And some went as far as to say, oh, well, all this pathology you see doesn’t matter. It’s an infection that does it.
Our study for the first time merges the two. It says, yes, let’s pay attention to these microbes that are accumulating in the brain as we age. But they’re accumulating, and they’re causing amyloid to form. And the emergence of the pathology is related to the fact that they’re getting into the brain. And until this point, they didn’t really have a cogent hypothesis of how infection might be involved.
Now, we do. And this is a high-risk project. But we’re very lucky to have foundations like Cure Alzheimer’s Fund, who want the out of the box stuff. You know? And we’ll do more out of the box stuff.
ROB: We will. And the other thing–
IRA FLATOW: Before you continue, just let me get this break in here, remind everybody that this is Science Friday from PRI, Public Radio International. Talking with Rob Moyer and Rudy Tanzi. Go ahead.
ROB: Yeah, and the other thing that has kind of held it up a bit is that in AD, you can find these bugs in Alzheimer’s disease, quite often many Alzheimer’s, but no single pathogen has been associated with 100% of Alzheimer’s disease patients. And that’s the kind of thing for most infectious diseases that people want to see.
But our kind of model says, well, you don’t need a single pathogen. You can have a whole bunch of different pathogens. It’s the inflammatory response that [INAUDIBLE] mediates that’s the problem.
IRA FLATOW: Well, what about if you prove the connection, how easy is it to treat it, then, with either anti-virals, anti-inflammatory drugs, or drugs to clear the amyloid?
RUDY TANZI: Well, right now, most of the therapies that we’re rating for readouts hit the amyloid. So the idea is to clear amyloid. And many of the earlier therapies that tried to clear amyloid failed, because they were treating full-blown patients. And the amyloid accumulates 10, 15, 20 years before symptoms. So it was like treating people who had heart attacks and congestive heart failure with statins for cholesterol.
We had to do that 10 years ago. So now, amyloid’s being treated much earlier. We’ll get those readouts over the next four years. So that’s called secondary prevention. They’re trying to reduce the pathology. Primary prevention would be, stop that pathology from occurring in the first place.
If amyloid is being driven in most people by the slow accumulation of microbes in the brain, then we can think about active immunization. We can think about anti-virals. We can think about new classes of antibiotics that get into the brain that Rob and I working on.
But first, we have to find out who the culprits are. I mean, our papers just said, yep, proof of concept– amyloids, antimicrobial. And these microbes can rapidly see the amyloid, even overnight. But now, we have to systematically study the brain from young to old to Alzheimer’s, and look in the plaques, and say, what’s living in there, and who are our suspects, and then we can really do the hard studies.
IRA FLATOW: But I would add to that that path may be quite a bit easier now that we’ve got the paper out, and guys like you are giving it air time. Well, I was going to say, you’ve gotten some positive reception. I’m pleasantly surprised to see that you got some.
RUDY TANZI: We are too.
ROB: Yeah, we are too.
RUDY TANZI: We were expecting the fall Schopenhauer. You know, Schopenhauer said, with any new discovery, first, is ridiculed, then violently opposed, and then taken to be self-evident. And so, we seemed to have skipped the ridicule part, which is nice.
ROB: There has been some pushback. But by and large, it’s been positive, so yeah.
IRA FLATOW: You know what they say, if you’re successful, it will have many fathers. And [INAUDIBLE]. Thank you, gentlemen. Thank you, doctors, for having having a talk with us. A very, very interesting conversation. Rob Moyer is neurobiologist is at Mass General, and Rudy Tanzi is a Professor of Neurology at the Harvard Med School, and Vice Chairman of Neurology at Mass General Hospital. Really close by. Thank you. Have a great holiday weekend for you.
ROB: Thank you. You’re welcome. And thank you.
IRA FLATOW: And good luck with your work.