By BRET STETKA —
It all started with genetic data.
A gene here, a gene there.
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.
Alzheimer’s commonality: excess amyloid
In a normal brain, a protein called beta-amyloid is cleared away through our lymphatic system by microglia as molecular junk.
But sometimes it builds up. Certain gene mutations 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.
The crowded Alzheimer’s gene scene
To date, nearly a dozen genes involved in immune and microglial function have been tied to Alzheimer’s.
The first was CD33, identified in 2008.
“When we got the results I literally ran to my colleague’s office next door and said you gotta see this!” says Harvard neuroscientist Rudolph Tanzi.
Tanzi, who goes by Rudy, led the CD33 research. The discovery was quickly named a top medical breakthrough of 2008 by Time magazine.
“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.”
A brake on overactive microglia
If CD33 is the yin, a gene called TREM2 is the yang.
Discovered a few years after CD33, TREM2 reins in microglial activation, returning them to their role as cellular housekeepers.
Neurologist David Holtzman 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.
