Alzheimer's disease may be caused by a hyperactive cell in the brain

By: April Carson



Genetic data was the beginning.


There are a lot of genes here and there.


Finally, the narrative became apparent: scientists should aim to study the immune system if they want to discover a cure for Alzheimer's disease one day.


Researchers have discovered numerous immune system genes that may be linked to Alzheimer's disease over the last several decades.


Genes that control tiny immune cells called microglia, which are now the focus of considerable study in creating new Alzheimer's medications, are among the top suspects.


Microglia are amoeba-like cells that search the brain for damage and intruders. They assist clear dead or malfunctioning neurons and devour invading pathogens by literally eating them up. We'd be in big trouble without them.


In a healthy brain, beta-amyloid is removed through the lymphatic system by microglia as molecular waste by a protein called beta-amyloid in a process known as autophagy.


Sometimes it builds up. One cause of poisonous build-up is certain gene mutations. Another reason for toxic accumulation is traumatic brain injury, and perhaps impaired microglial function.


One thing that everyone seems to agree on is that too much amyloid builds up between brain cells and blood vessels in people suffering from Alzheimer's.


The accumulation of another protein, called tau, inside brain cells once amyloid begins to block networks of neurons. Tau activation drives microglia and other immune responses into overdrive, triggering the inflammatory immune response that many experts believe eventually drains brain vitality in Alzheimer's.


The gene scene


To date, over a dozen genes connected with immune and microglial function have been linked to Alzheimer's disease.


The first was CD33, which was discovered in 2008.


"When we got the test results, I immediately ran to my colleague's office next door and exclaimed, 'You've gotta see this!,' according to Harvard neuroscientist Rudolph Tanzi.


The CD33 research was led by Tanzi, who goes by Rudy. Time magazine named the discovery a top medical breakthrough of 2008 in its issue dated June 4th.


"We were giggling because we had no clue what this gene did," he says with a chuckle.


CD33 is a kind of microglial on-off switch that activates cells as part of an inflammatory reaction, according to Tanzi's research.


"When it came to the genetics, we had everything going," he adds.


Microglia are capable of detecting molecular patterns associated with microbes and cell damage as "harmful." This is how they learn to act - to devour unfamiliar pathogens and necrotic tissue. Tanzi thinks that microglia detect any sign of brain damage as an infection, causing them to become hyperactive.


Many hundreds of thousands of years ago, our modern human immune system developed. Our lifespans were much shorter then and the majority of people did not live long enough to get dementia or the withered brain cells that come with it. According on his theory, our immune mechanism assumes any faulty brain tissue is caused by a microbe rather than dementia.


"They say, 'We've got to get rid of this damaged brain component, no matter what,' says Tanzi. "This is when neuroinflammation kicks in. CD33 activates this response. In this case, the microglia become executioners rather than cleaners."


A brake on overactive microglia


TREM2 is the gene that's opposite in function to CD33, which makes it the yang.


TREM2 was identified several years after CD33, when researchers observed that it inhibits microglial activation and restrains them from becoming overactive.


Neurologist David Holtzman of Washington University in St. Louis, who is interested in TREM2, concurs that microglia may be active when you identify amyloid, tau, or dead brain cells.


"I think many persons at first assumed these cells were reacting to Alzheimer's disease rather than being a cause of it," he adds.


It was the finding of TREM2, followed by CD33, that really changed things for me, in part because it makes a protein only found in microglia in the brain. Genes are segments of DNA that encode proteins that actually operate our bodies and brains.


Many of us [in the field] immediately guessed that there was a new, previously unknown risk element present in microglia. So it must be that innate immune cells are crucial in some manner to the disease's development," he continues.


In the present study, researchers sought to define microglial activation in Alzheimer's disease. Microglia are activated early on in the course of Alzheimer's disease, according to Holtzman. However, once enough amyloid and tau have damaged the brain, neuroinflammation provoked by microglial activation does more harm than good. The death of millions of neurons leads to dementia.


Not all experts are persuaded.


Serge Revist is a molecular medicine professor at Laval University Medical School in Quebec. Based on his lab's findings, he thinks that while Alzheimer's disease is associated with an impaired immune response, it isn't the underlying cause. "I don't believe it's the immune cells themselves that damage neurons; rather, I still believe it's beta-amyloid," he adds.


Dr. Smith does not believe that inhibiting microglia in the brain will be beneficial because there are cases where he thinks they may not be able to handle all of the amyloid that builds up during Alzheimer's disease. He feels that developing treatments to enhance microglial and immunological clearance of protein might help.


Microglial medicines


It's a complicated biological chain that begins with Alzheimer's Disease.

The accumulation and clearance of amyloid are influenced by multiple genetic variants. However, the immune response triggered by an infection in early life is likely to be involved, at least in some situations. Robert Moir, now deceased Tanzi's former colleague, proposed this contagious Alzheimer's theory. The amyloid produced by the brain may have originally protected us from disease but has since become harmful when overactive and aggregated, according to Tanzi's group.


The same can be said for microglia, which may cause much of the brain deterioration seen in Alzheimer's disease.


In theory, if a therapy could decrease CD33 activity, or increase TREM2 activity, doctors may one day be able to slow or even stop the progression of dementia. Instead of attempting to attack amyloid directly, a treatment that dampens the immune response to it may be useful in treating Alzheimer's disease.


"There are many scientists and firms searching for a way to change genes like TREM2 and CD33 in order to reduce amyloid while also acting on the protein's downstream outcomes," says Holtzman. "The purpose of this is to emphasize that the immune system is involved in some part of the biology that causes Alzheimer's.


It appears that in many situations, a well-intentioned immune cell going astray is the most typical type of dementia.


"I believe that any serious researcher would tell you the same thing," adds Tanzi. "Without microglial activation, I am certain that Alzheimer's disease will not develop."






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About the Blogger:


April Carson is the daughter of Billy Carson. She received her bachelor's degree in Social Sciences from Jacksonville University, where she was also on the Women's Basketball team. She now has a successful clothing company that specializes in organic baby clothes and other items. Take a look at their most popular fall fashions on bossbabymav.com


To read more of April's blogs, check out her website! She publishes new blogs on a daily basis, including the most helpful mommy advice and baby care tips! Follow on IG @bossbabymav


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