Overview: Researchers have identified a protein that microglia in the brain can utilize to help stave off Alzheimer’s and other neurodegenerative diseases.
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many neurodegenerative diseasesor conditions resulting from loss of function or death of brain cells, remain largely untreatable. just one of several processes It can lead to neurodegeneration and, if at all, may not be effective in fully addressing the symptoms and progression of the disease.
But what if researchers harnessed the brain’s innate ability to cleanse and heal itself? My colleague and me in the Luken’s Lab Doctors at the University of Virginia believe that the brain’s own immune system may hold the key to treating neurodegenerative diseases.in us researchimmune cells in the brain, or microglia could be harnessed to help stave off Alzheimer’s disease.
Challenges in treating neurodegeneration
There are no available treatments for neurodegenerative diseases that stop ongoing neurodegeneration while helping the body heal and repair the affected areas.
In terms of treatment failure, Alzheimer’s disease is perhaps the most notorious neurodegenerative disease.influence More than 1 in 9 U.S. adults over the age of 65Alzheimer’s disease is the result of brain atrophy with the death of neurons and loss of connections between them. These casualties contribute to memory and cognitive decline. billions of dollars Research into a cure for Alzheimer’s disease has been pouring in, but nearly every drug tested so far has failed in clinical trials.
Another common neurodegenerative disease in need of improved treatment options is multiple sclerosisThis autoimmune condition is caused by immune cells attacking the protective covering of neurons known as myelin. When myelin breaks down, it becomes difficult for neurons to connect with the rest of the body.
current treatment It can suppress the immune system and cause debilitating side effects. Many of these treatment options fail to address the toxic effects of myelin debris that accumulates in the nervous system, which can kill cells.
A new frontier in neurodegenerative therapy
microglia are immune cells Pretending to be brain cells. in the mouse, microglia originate from the yolk sac of the embryo and invade the brain early in development.Origin and migration of microglia in person Still researching.
Microglia play an important role in healthy brain function. Like other immune cells, microglia respond rapidly to pathogens and damage. They help remove damage and repair diseased tissue, and can also play an active role in fighting pathogens.Microglia can also cause swelling and damage if left unchecked. It can also modulate inflammation in the brain, which is a normal part of the immune response.
Microglia also support the health of other brain cells.For example they can Releases molecules that promote resiliencesuch as BDNF, a protein known to be beneficial for neuronal survival and function.
However, the key feature of microglia is their surprising features. janitor skillsOf all brain cell types, microglia are excellent at cleaning up gunk in the brain, such as the damaged myelin in multiple sclerosis, dead cell debris, and amyloid beta, a toxic protein that is hallmark of Alzheimer’s disease. They achieve this by consuming and decomposing debris within their environment, effectively devouring surrounding debris and adjacent cells.
Given the many critical roles that microglia help maintain brain function, these cells may have the capacity to address multiple areas of neurodegeneration-related dysfunction. Moreover, as lifelong inhabitants of the brain, microglia are already educated in brain protection best practices. These factors put microglia in the best position for researchers to harness their unique abilities to protect against neurodegeneration.
new data In both animal models and human patients, we point to a previously underappreciated role of microglia in the development of neurodegenerative diseases as well.Many genetic risk factors for diseases such as Alzheimer’s disease When multiple sclerosis It is strongly associated with abnormal microglial function. These findings are Cumulative number of animal experiments It suggests that disruption of microglial function may contribute to the development and severity of neurological disease.
This raises the logical question: How can researchers harness microglia to protect the nervous system from neurodegeneration?
Use the magic of microglia
In our laboratory Recent researchwe focused on a key protein called SYK that microglia use to manipulate their response to neurodegeneration.
Our collaborators discovered that microglia Dial up SYK activities When you encounter debris around you, such as amyloid beta in Alzheimer’s disease or myelin debris in multiple sclerosis. Inhibition of her SYK function in microglia was found to accumulate twice as much amyloid-beta in an Alzheimer’s disease mouse model and six times more myelin debris in a multiple sclerosis mouse model.
Blocking SYK function in microglia in a mouse model of Alzheimer’s disease also worsened neuronal health, increasing levels of toxic neuronal proteins and showing a sharp increase in the number of dying neurons. . This correlated with accelerated cognitive decline as mice failed to learn spatial memory tests.
Similarly, impairing SYK in a mouse model of multiple sclerosis exacerbated motor dysfunction and interfered with myelin repair. These findings indicate that microglia use her SYK to protect the brain from neurodegeneration.
But how does SYK protect the nervous system from damage and degeneration? Microglia have been found to use SYK to move towards debris in the brain. It also helps microglia remove and destroy this debris by stimulating other proteins involved in the cleanup process. These work support the idea that SYK helps protect the brain by charging microglia and removing toxic substances.
Finally, we wanted to see if SYK could be harnessed to create ‘super microglia’ that help clean up debris before it worsens neurodegeneration. In a mouse model of Alzheimer’s disease, one week after administration of the drug, levels of plaque accumulation in the brain were found to decrease. This finding points to the potential of increasing microglial activity to treat Alzheimer’s disease.
Horizons of microglial therapy
Future research is needed to see if creating a super microglial cleanup crew to treat neurodegenerative diseases would benefit people. However, our results suggest that microglia already play an important role in the prevention of neurodegenerative diseases by helping remove toxic wastes from the nervous system and promoting healing of damaged areas. increase.
However, there can be too many good ones. excessive inflammation Driven by microglia can exacerbate neurological disorders. We believe that giving microglia the proper instructions to perform their beneficial functions without causing further damage will one day aid in the treatment and prevention of neurodegenerative diseases.
Funding: This work was supported by funding from the NIH (1RF1AG071996-01, R01NS106383), the Alzheimer’s Society (ADSF-21-816651), the CURE Alzheimer’s Disease Foundation, the Owens Family Foundation, and the Wagner Scholarship.
About this immune system and neurodegeneration research news
author: Christine Zengeler
sauce: conversation
contact: Kristin Zengeler – The Conversation
image: image is public domain
