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Scientists Explore Ties Between Alzheimer's And Brain's Ancient Immune System

Feb 18, 2018
Originally published on March 24, 2018 7:24 am

Beer has fueled a lot of bad ideas. But on a Friday afternoon in 2007, it helped two Alzheimer's researchers come up with a really a good one.

Neuroscientists Robert Moir and Rudolph Tanzi were sipping Coronas in separate offices during "attitude adjustment hour" at Massachusetts General Hospital, Harvard's largest teaching hospital. And, by chance, each scientist found himself wondering about an apparent link between Alzheimer's disease and the immune system.

Moir had been surfing through random scientific papers online — something he does for an hour or so on most Fridays. "I cruise wherever my fancy takes me," he says.

And on this day, he cruised to research on molecules known as antimicrobial peptides. They're part of the ancient immune system that's found in all forms of life and plays an important role in protecting the human brain.

One way antimicrobial peptides protect us is by engulfing and neutralizing a germ or some other foreign invader. That gives newer parts of the immune system time to get mobilized.

These peptides are "extremely important," Moir says. "They're not like legacies from an immune system we don't use anymore. If you don't have them, you're going to die in a couple of hours."

As Moir surfed through paper after paper, he realized that one of these ancient molecules, known as LL-37, looked a lot like a molecule closely associated with Alzheimer's. That molecule is called amyloid-beta and it forms the sticky plaques that tend to build up in the brains of people with dementia.

LL-37 and Amyloid-beta "looked just like peas in a pod," Moir says.

That was really surprising. Even more surprising, on that same Friday afternoon, Moir's colleague Tanzi had also noticed a connection between Alzheimer's and the ancient immune system, which scientists refer to as innate immunity.

Tanzi had been spending the same hour that Friday afternoon reviewing a list of genes he'd found that were somehow related to Alzheimer's. "I was enjoying my first or second Corona," he says, "and I noticed that many of the genes coming up were involved with innate immunity."

"I was like, well, what does that mean?" Tanzi says. "So I wandered into [Moir's] office, carrying my Corona in hand, and I said, 'What do you know about innate immunity in the brain?' "

The two researchers decided to team up to figure out precisely how innate immunity figures into Alzheimer's. They later sketched out their research plan while sipping Bordeaux on the deck of Tanzi's house along the coast.

"We spent a lot of evenings out there making a dent in his very nice cellar," Moir says.

The two scientists began to discuss a wild idea. What if amyloid-beta was an integral part of the ancient immune system? What if those sticky plaques were actually an effort to protect the brain by encapsulating foreign invaders?

Their idea was that the brain was producing amyloid for much the same reason an oyster forms a pearl — for self-defense. "Maybe amyloid plaques are a brain pearl," Moir says, "a way for our body to trap and permanently sequester these invading pathogens."

That was a pretty radical idea. For decades, most scientists thought amyloid-beta was no more than a toxic waste product. "In all those scenarios it's bad, bad, bad, bad, bad," Moir says.

But Moir and Tanzi suspected amyloid-beta was usually good — unless the brain started making too much. Then it could kill brain cells and lead to dementia.

This hypothesis was not immediately embraced by other scientists, Tanzi says.

"I had folks emailing me, ex-mentors — Nobel laureates — saying, 'Rudy have you lost your mind?' Luckily neither Rob nor I have a really good track record of listening to people."

So. Tanzi and Moir set out to prove that amyloid really is part of the immune system. And they were lucky enough to have a funder, the Cure Alzheimer's Fund, that was willing to take a chance on their idea.

The effort took years. But in 2010, Moir, Tanzi, and their team demonstrated that amyloid is really good at killing viruses and bacteria in a test tube. And, in 2016, they showed it did the same thing in worms and mice.

"It was very clear that amyloid protected against infection," Tanzi says. "If a mouse had meningitis or encephalitis, [and] if that mouse was making amyloid it lived longer." In contrast, mice that did not produce amyloid died quickly from the infection.

Today, Tanzi and Moir's wild idea is no longer considered so wild. Lots of scientists are now studying the ancient immune system's connection to Alzheimer's.

And Tanzi says it's become clear that Alzheimer's involves a lot more than just plaques and tangles in the brain.

"Even though we really concentrate on these plaques and tangles in Alzheimer's disease, it looks like it's the brain's immune system — the very primitive immune system of the brain — that's gone awry," Tanzi says, "and the plaques and tangles are a part of that system."

The question now is: What's causing the glitch in the ancient immune system?

One possibility is that it's overreacting to viruses and bacteria that get into the brain. Or, the system could be getting confused and attacking healthy cells — a lot like what happens in diseases like lupus or multiple sclerosis.

If either idea holds up, it may be possible to interrupt the process before it causes Alzheimer's, Moir says. "That's a pretty good outcome from a couple of Coronas 10 years ago."

Copyright 2018 NPR. To see more, visit http://www.npr.org/.

SCOTT SIMON, HOST:

A new breakthrough may have emerged from research into Alzheimer's disease and it popped up, if you please, during cocktail hour over some beer and Bordeaux. NPR's Jon Hamilton tells us how two scientists found a surprising link between Alzheimer's and an ancient part of the immune system.

JON HAMILTON, BYLINE: Fear has fueled a lot of bad ideas. But in 2007, it led to a good one.

ROB MOIR: The story from my side starts at attitude readjustment hour.

HAMILTON: Rob Moir studies Alzheimer's disease at Harvard Medical School in Massachusetts General Hospital. It was a Friday afternoon, so Moir was sipping a Corona and being a scientist, he was also surfing random scientific papers online.

MOIR: I cruise wherever my fancy takes me.

HAMILTON: On this day, it took him to some ancient molecules that are still present in the immune system.

MOIR: They've been around 500 million years.

HAMILTON: Moir says one thing these ancient molecules do is wrap themselves around any germ they see. This encapsulates the invader until newer parts of the immune system can get mobilized.

MOIR: They're extremely important. They're not like legacies from an immune system we don't use anymore. If you don't have them, you're going to die in a couple of hours.

HAMILTON: As Moir read paper after paper, he realized that one of these ancient molecules was nearly identical to a molecule he sees everyday.

MOIR: It looks just like peas in a pod.

HAMILTON: It's called amyloid. And in people with Alzheimer's, amyloid molecules clumped together to form sticky plaques. So there's striking similarity to a molecule that fights infection was really surprising. Even more surprising on that same Friday afternoon, another Alzheimer's researcher was also drinking Coronas and pondering the immune system.

RUDY TANZI: I was going go over gene data in my office right next to Rob's.

HAMILTON: Rudy Tanzi was reviewing a list of genes he'd found that were somehow related to Alzheimer's.

TANZI: I noticed that many of the genes coming up were involved with innate immunity.

HAMILTON: Innate immunity is the fancy scientific name for the ancient immune system.

TANZI: And I was like, what does that mean? So I wondered into Rob's office carrying my Corona in hand. And I said, what do you know about innate immunity in the brain?

HAMILTON: The scientists decided to team up. Moir says they came up with a plan while sipping wine on the deck of Tanzi's house along the coast.

MOIR: And we spent a lot of evenings out there making a dent in his very nice cellar.

TANZI: Rob, they're going to think we're a couple of lushes. I mean, you know, it was good Bordeaux - much better than the Corona, but...

HAMILTON: The two men began to discuss a wild idea. What if amyloid was a part of the ancient immune system? Would have its purpose was to protect the brain by wrapping up foreign invaders? Moir says they suspected that the brain produced amyloid for the same reason an oyster forms a pearl.

MOIR: May be amyloid plaques are a brain pool and a way for our body to trap and permanently sequester these invading pathogens.

HAMILTON: It was a pretty radical idea. For decades, most scientists thought amyloid was just a toxic waste product.

MOIR: In all those scenarios, it's bad, bad, bad, bad.

HAMILTON: But Moir and Tanzi thought amyloid was usually good, unless the brain made too much. Then, it could kill brain cells and lead to dementia. Tanzi says that idea was not well received by other scientists.

TANZI: I had folks emailing me - ex-mentors, Nobel lawyers saying, Rudy, have you lost your mind?

HAMILTON: So Tanzi and Moir set out to prove that amyloid really was part of the immune system.

TANZI: Luckily, neither Rob nor I really have a good track record of listening to people.

HAMILTON: The effort took years. But in 2010, Moir and Tanzi showed that amyloid was really good at killing germs in a test tube. And in 2016, they showed it did the same thing in worms and mice.

TANZI: It was very clear that amyloid protected against infection. That if a mouse had meningitis or encephalitis - if that mouse was making amyloid, it lived longer.

HAMILTON: Today, lots of scientists are studying the link between the ancient immune system and Alzheimer's. And Tanzi says it's become clear that Alzheimer's involves a lot more than just plaques and tangles in the brain.

TANZI: Even though we really concentrate on these plaques and tangles in Alzheimer's disease, it looks like it's the brain's immune system - the very primitive immune system of the brain that's going awry. And the plaques and tangles are part of that system.

HAMILTON: The question now is what's going wrong? It could be that the ancient immune system is overreacting to viruses or bacteria that get into the brain. Or maybe it's confused and is attacking healthy cells, a lot like what happens in diseases like lupus or multiple sclerosis. Moir says if either of those ideas is right, it may be possible to interrupt the process before it leads to Alzheimer's.

MOIR: That's a pretty good outcome from a couple of Coronas 10 years ago (laughter).

HAMILTON: Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.