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Eventually the story became clearer: If scientists are to one day find a cure for Alzheimer's disease, they should look to the immune system.  

Over the past couple decades, researchers have identified numerous genes involved in various immune system functions that may also contribute to Alzheimer's. 

Some of the prime suspects are genes that control humble little immune cells called microglia, now the focus of intense research in developing new Alzheimer's drugs. 

Microglia are amoeba-like cells that scour the brain for injuries and invaders. They help clear dead or impaired brain cells and literally gobble up invading microbes. Without them, we'd be in trouble. 

In a normal brain, a protein called beta-amyloid is cleared away through our lymphatic system by microglia as molecular junk. 

 are one culprit in this toxic accumulation. Traumatic brain injury is another, and, perhaps, impaired microglial function.

One thing everyone agrees on is that in people with Alzheimer's, too much amyloid accumulates between their brain cells and in the vessels that supply the brain with blood.

Once amyloid begins to clog networks of neurons, it triggers the accumulation of another protein, called tau, inside of these brain cells. The presence of tau sends microglia and other immune mechanisms into overdrive, resulting in the inflammatory immune response that many experts believe ultimately saps brain vitality in Alzheimer's. 

To date, nearly a dozen genes involved in immune and microglial function have been tied to Alzheimer's. 

"When we got the results I literally ran to my colleague's office next door and said you gotta see this!" says Harvard neuroscientist 

Tanzi, who goes by Rudy, led the CD33 research. The discovery was quickly named a top medical breakthrough of 2008 by 

"We were laughing because what they didn't know is we had no idea what this gene did," he jokes. 

But over time, research by Tanzi and his group revealed that CD33 is a kind of microglial on-off switch, activating the cells as part of an inflammatory pathway. 

"We kind of got it all going when it came to the genetics," he says. 

Microglia normally recognize molecular patterns associated with microbes and cellular damage as unwanted. This is how they know to take action – to devour unfamiliar pathogens and dead tissue. Tanzi believes microglia sense any sign of brain damage as an infection, which causes them to become hyperactive. 

Much of our modern human immune system, he explains, evolved many hundreds of thousands of years ago. Our lifespans at the time were far shorter than they are today, and the majority of people didn't live long enough to develop dementia or the withered brain cells that comes with it. So our immune system, he says, assumes any faulty brain tissue is due to a microbe, not dementia. Microglia react aggressively, clearing the area to prevent the spread of infection. 

"They say, 'We better wipe out this part of the brain that's infected,’ even if it's not. They don't know," quips Tanzi. "That's what causes neuroinflammation. And CD33 turns this response on. The microglia become killers, not just janitors." 

Discovered a few years after CD33, TREM2 reins in microglial activation, returning them to their role as cellular housekeepers. 

 of Washington University in St. Louis, who studies TREM2, agrees that where you find amyloid, tau or dead brain cells, there are microglia, raring to go and ready to scavenge. 

"I think at first a lot of people thought these cells were reacting to Alzheimer's pathology, and not necessarily a cause of the disease," he says.

It was the discovery of TREM2 on the heels of CD33 that really shifted the thinking, in part because it produces a protein that in the brain is only found in microglia. Genes are stretches of DNA that encode for the proteins that literally run our bodies and brains. 

"Many of us [in the field] immediately said 'Look, there's now a risk factor that is only expressed in microglia. So it must be that innate immune cells are important in some way in the pathogenesis of the disease," he adds. 

Holtzman sees microglial activation in impending dementia as a double-edged sword. In the beginning, microglia clear unwanted amyloid to maintain brain health. But once accumulated amyloid and tau have done enough damage, the neuroinflammation that comes with microglial activation does more harm than good. Neurons die 

Serge Revist is a professor in the Department of Molecular Medicine at the Laval University Medical School in Quebec. Based on his lab's research, he believes that while impaired immune activity is involved in Alzheimer's, it's not the root cause. "I don't think it's the immune cells that do the damage, I still think it's the beta-amyloid itself," he says, "In my lab, in mouse studies, we've never found that immune cells were directly responsible for killing neurons."

He does believe that in some Alzheimer's patients microglia may not be able to handle the excess amyloid that accumulates in the disease, and that developing treatments that improve the ability of microglia and the immune system to clear the protein could be effective. 

The biological cascade leading to Alzheimer's is a tangled one. 

Gene variants influencing the accumulation and clearance of amyloid are likely a major contributor. But immune activity caused by early life infection might also be involved, at least in some cases. This infectious theory of Alzheimer's was first proposed by Tanzi's now-deceased colleague Robert Moir. Tanzi's group even has evidence that amyloid itself is antimicrobial, and evolved to protect us from pathogens, only to become a problem when overactive and aggregated. 

And the same goes for microglia, cells whose over-ambition might cause much of the brain degeneration seen in Alzheimer's. 

In theory, if a treatment could, say, decrease CD33 activity, or increase that of TREM2, doctors might one day be able to slow or even stop the progression of dementia. Instead of going after amyloid itself – the mechanism behind so many failed investigational Alzheimer's drugs – a therapy that quells the immune response to amyloid might be the answer in treating dementia. 

"There are number of scientists and companies trying to figure out how to influence genes like TREM2 and CD33, and to both decrease amyloid and act on the downstream consequences of the protein," says Holtzman. "All of this is to say that somewhere in the biology that causes Alzheimer's the immune system is involved." 

It seems that in many cases the most common form of a dementia might be due to a well-intentioned immune cell going rogue. 


"I think you'd hear this from basically any researcher worth their salt," says Tanzi. "I feel strongly that without microglial activation, you will not get Alzheimer's disease."


Health

Bret Stetka

Author

Microglia are amoeba-like cells that scour the brain for injuries and invaders. But sometimes the usually helpful cells go into overdrive and damage the brain, researchers say. 

How a hyperactive cell in the brain might trigger Alzheimer's disease

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