Using the brain’s immune cells to combat Alzheimer’s disease and other neurodegenerative diseases
Abstract: Researchers have identified a protein that could be used to help microglia in the brain prevent Alzheimer’s disease and other neurodegenerative diseases.
Many neurodegenerative diseases, or conditions resulting from the loss of function or death of brain cells, remain largely incurable. Most available treatments target just one of many processes this can lead to neurodegeneration, which may not be effective in completely resolving disease symptoms or progressing, if at all.
But what if researchers harnessed the brain’s inherent ability to clean and heal itself? My colleagues me too in Lukens Laboratory at the University of Virginia believe that the brain’s own immune system may hold the key to treating neurodegenerative diseases. In ours Researchwe found a protein that could be used to help the brain’s immune cells, or microglia, fight off Alzheimer’s disease.
Challenges in the treatment of neurodegeneration
There are no treatments available for neurodegenerative diseases that halt ongoing neurodegeneration while helping the affected areas of the body to heal and recover.
In terms of failed treatments, Alzheimer’s disease is perhaps the most notorious neurodegenerative disease. Influencing more than 1 in 9 US adults age 65 and older, Alzheimer’s is the result of brain atrophy with the death of neurons and the loss of connections between them. These losses contribute to memory and cognitive decline. Billions of dollars are focused on researching treatments for Alzheimer’s disease, but almost every drug tested to date has failed in clinical trials.
Another common neurodegenerative disease in need of improved treatment options is Multiple sclerosis. This autoimmune condition is caused by immune cells attacking neurons’ protective covering, known as myelin. The breakdown of myelin leads to difficulties in communication between neurons and their connections with the rest of the body.
Instant treatments they suppress the immune system and can have potentially debilitating side effects. Many of these treatment options do not address the toxic effects of myelin debris that accumulates in the nervous system, which can kill cells.
A new frontier in the treatment of neurodegeneration
They are microglia immune cells masquerading as brain cells. In mice, microglia originate in the yolk sac of the embryo and then infiltrate the brain early in development. Origin and migration of microglia in people are still in the study phase.
Microglia play an important role in healthy brain function. Like other immune cells, microglia respond quickly to pathogens and damage. They help to remove injuries and heal the affected tissue, and can also take an active role in the fight against pathogens. Microglia can also regulate brain inflammation, a normal part of the immune response that can cause swelling and damage if left unchecked.
Microglia also support the health of other brain cells. For example, I can they release molecules that promote resistancesuch as the protein BDNF, which is known to be beneficial for the survival and functioning of neurons.
But the key feature of microglia is their amazingness janitorial skills. Of all the types of brain cells, microglia have a remarkable ability to clean up brain debris, including the damaged myelin of multiple sclerosis, bits of dead cells, and amyloid beta, the toxic protein that is the hallmark of Alzheimer’s disease. They achieve this by consuming and breaking down the waste in their environment, effectively eating the garbage that surrounds them and their neighboring cells.
Given the many essential roles that microglia serve to maintain brain function, these cells may have the ability to address the multiple arms of dysfunction associated with neurodegeneration. Moreover, as lifelong residents of the brain, microglia are already educated in the best practices of brain protection. These factors put microglia in a perfect position for researchers to exploit their inherent abilities to protect against neurodegeneration.
New data in both animal models and human patients indicates a previously underappreciated role that microglia also play in the development of neurodegenerative diseases. Many genetic risk factors for diseases such as Alzheimer’s disease and Multiple sclerosis are strongly associated with abnormal microglia function. These findings support the an collecting number of animal studies suggesting that disturbances in microglia function may contribute to the onset and severity of neurological diseases.
This raises the next logical question: How can researchers use microglia to protect the nervous system from neurodegeneration?
Tapping into the magic of microglia
In our laboratory a recent studywe included a key protein called SYK that microglia use to manipulate the response to neurodegeneration.
Our colleagues discovered that microglia dial up activity SYK when they encounter debris in their environment, such as amyloid beta in Alzheimer’s disease or myelin debris in multiple sclerosis. When we inhibited SYK function in microglia, we found that twice as much amyloid beta accumulated in mouse models of Alzheimer’s disease and six times as much myelin debris in mouse models of multiple sclerosis.
Blocking SYK function in microglia in mouse models of Alzheimer’s disease also worsened neuronal health, as indicated by increased levels of toxic neuronal proteins and an increase in the number of dying neurons. This was associated with accelerated cognitive decline, as the mice failed to learn the spatial memory test.
Similarly, knockdown of SYK in multiple sclerosis mouse models exacerbated motor dysfunction and prevented myelin repair. These findings indicate that microglia use SYK to protect the brain from neurodegeneration.
But how does SYK protect the nervous system from damage and degeneration? We found that microglia use SYK to migrate toward brain debris. It also helps microglia remove and destroy this waste by stimulating other proteins involved in the cleaning processes. These works support the idea that SYK helps microglia protect the brain by prompting them to remove toxic materials.
Finally, we wanted to find out if we could use SYK to create “super microglia” that could help clean up debris before it worsened neurodegeneration. When we gave mice a drug that boosted SYK function, we found that mouse models of Alzheimer’s disease had lower levels of plaque build-up in the brain a week after receiving the drug. This discovery points to the potential of increasing the activity of microglia in the treatment of Alzheimer’s disease.
Microglia Treatment Horizon
Future studies will be needed to see if creating a team to clean up super microglia to treat neurodegenerative diseases is beneficial in humans. But our results suggest that microglia already play a key role in the prevention of neurodegenerative diseases by helping to remove toxic waste from the nervous system and promoting healing of damaged areas.
However, it is possible to have too much of a good thing. Excessive inflammation driven by microglia could worsen neurological diseases. We believe that equipping microglia with the proper instructions to perform their beneficial functions without causing further harm could one day help in the treatment and prevention of neurodegenerative diseases.
Financing: This work was funded by the NIH (1RF1AG071996-01, R01NS106383), the Alzheimer’s Association (ADSF-21-816651), the Alzheimer’s Disease Cure Fund, the Owens Family Foundation, and a Wagner Fellowship
About this immune system and neurodegeneration research news
Author: Kristina Zengeler
Contact: Kristine Zengeler – Interview
Picture: The image is in the public domain