Many neurodegenerative diseases, or conditions resulting from the loss of function or death of brain cells, remain largely incurable. Most available treatments target only one of the multiple processes that can lead to neurodegeneration, which may not be effective in treating symptoms or disease progression completely, if at all.
But what if researchers harnessed the brain’s inherent abilities to cleanse and heal itself? My colleagues and I at the University of Virginia’s Lukens Lab believe that the brain’s immune system may hold the key to treating neurodegenerative diseases. In our research, we found a protein that could potentially be used to help immune cells in the brain, or microglia, ward off Alzheimer’s disease.
The Challenges of Treating Neurodegeneration
No treatment available for neurodegenerative diseases stops ongoing neurodegeneration while helping affected areas of the body to heal and recover.
In terms of treatment failures, Alzheimer’s disease is perhaps the most infamous of the neurodegenerative diseases. Affecting more than 1 in 9 American adults aged 65 and over, Alzheimer’s disease results from brain atrophy with the death of neurons and loss of connections between them. These losses contribute to memory and cognitive decline. Billions of dollars have been invested in research into treatments for Alzheimer’s disease, but nearly every drug tested to date has failed in clinical trials.
Multiple sclerosis is another common neurodegenerative disease requiring improved treatment options. This autoimmune disease is caused by immune cells that attack the protective covering of neurons, known as myelin. The breakdown of myelin leads to difficulties in communication between neurons and their connections with the rest of the body. Current treatments suppress the immune system and can have potentially debilitating side effects. Many of these treatment options fail to address the toxic effects of myelin debris that builds up in the nervous system, which can kill cells.
A new frontier in the treatment of neurodegeneration
Microglia are immune cells masquerading as brain cells. In mice, microglia originate in the yolk sac of an embryo and then infiltrate the brain during early development. The origins and migration of microglia in humans are still under investigation.
Microglia play an important role in the proper functioning of the brain. Like other immune cells, microglia respond quickly to pathogens and damage. They help eliminate injuries and repair affected tissues, and can also play an active role in fighting 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, they can release molecules that promote resilience, such as the BDNF protein, which is known to benefit neuron survival and function.
But the keystone of Microglia is its incredible janitorial skills. Of all types of brain cells, microglia have an exquisite ability to clean up grime in the brain, including damaged myelin in multiple sclerosis, bits of dead cells, and beta-amyloid, a toxic protein characteristic of Alzheimer’s disease. They accomplish this by consuming and breaking down debris in their environment, effectively eating the garbage around them and their neighboring cells.
Given the many critical roles microglia play in maintaining brain function, these cells may possess the ability to address multiple arms of neurodegeneration-related dysfunction. Additionally, as permanent residents of the brain, microglia are already trained in brain protection best practices. These factors put microglia in the perfect position for researchers to leverage their inherent abilities to protect against neurodegeneration.
New data from animal models and human patients indicate that microglia also play a previously underestimated role in the development of neurodegenerative diseases. Many genetic risk factors for diseases like Alzheimer’s disease and multiple sclerosis are strongly linked to abnormal microglia function. These findings support a growing number of animal studies suggesting that disturbances in microglial function may contribute to the onset and severity of neurological disease.
This raises the following logical question: how can researchers harness microglia to protect the nervous system against neurodegeneration?
Engage the magic of microglia
In our lab’s recent study, we looked at a crucial protein called SYK that microglia use to manipulate its response to neurodegeneration.
Our collaborators discovered that microglia increase SYK activity when they encounter debris in their environment, such as beta-amyloid in Alzheimer’s disease or myelin debris in multiple sclerosis. When we inhibited SYK function in microglia, we found that twice as much beta-amyloid accumulated in mouse models with Alzheimer’s disease and six times as much myelin debris in mouse models with Alzheimer’s disease. multiple sclerosis.
Blocking SYK function in the microglia of Alzheimer’s mouse models also worsened neuronal health, indicated by increasing levels of toxic neuronal proteins and an increase in the number of dying neurons. This correlated with accelerated cognitive decline, as the mice failed to learn a spatial memory test. Similarly, alteration of SYK in mouse models with multiple sclerosis exacerbated motor dysfunction and impeded myelin repair. These results indicate that microglia use SYK to protect the brain from neurodegeneration.
But how does SYK protect the nervous system against damage and degeneration? We found that microglia use SYK to migrate to debris in the brain. It also helps microglia clear and destroy this debris by stimulating other proteins involved in cleaning processes. These jobs support the idea that SYK helps microglia protect the brain by instructing them to remove toxic materials.
Finally, we wanted to know if we could leverage SYK to create a “super microglia” that could help clean up debris before it worsens neurodegeneration. When we gave mice a drug that boosted SYK function, we found that the Alzheimer’s mouse models had lower levels of plaque buildup in their brains one week after receiving the drug. This finding indicates the potential for increased microglia activity to treat Alzheimer’s disease.
The horizon of treatments for microglia
Future studies will be needed to see if creating a super microglia cleanup team to treat neurodegenerative diseases is beneficial in humans. But our results suggest that microglia already play a key role in preventing neurodegenerative diseases by helping to remove toxic waste from the nervous system and promoting healing of damaged areas.
It’s possible to have too much of a good thing, however. Excessive inflammation caused by microglia could worsen neurological disease. We believe that equipping microglia with the proper instructions to perform its beneficial functions without causing further harm could one day help treat and prevent neurodegenerative diseases.
Listen to The Conversation Uncharted Brain: Decoding Dementia podcast series to learn about the latest research that uncovers clues to the lingering mystery of how dementia works in the brain. Find all the episodes via The Anthill podcast.
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