“With this study, we’ve found a way to potentially harness microglia themselves to treat those diseases,” said Mathew Blurton-Jones of UCI (clockwise from upper left), pictured with Jean Paul Chadarevian of UCI, and Frederick “Chris” Bennett and Sonia Lombroso of Penn.
Combating Alzheimer’s and other neurodegenerative diseases by inserting healthy new immune cells into the brain has taken a leap toward reality.
Neuroscientists at the University of California, Irvine and the University of Pennsylvania have found a way to safely thwart the brain’s resistance to them, vaulting a key hurdle in the quest.
Their discovery about brain cells called microglia heralds myriad possibilities for treating and even preventing neurodegenerative disorders. The team’s paper appears in the Journal of Experimental Medicine.
Link to study: https://rupress.org/jem/article/220/3/e20220857/213788/Engineering-an-inhibitor-resistant-human-CSF1R
When microglia are healthy, they serve as the central nervous system’s resident front-line disease warriors. “However, there is overwhelming evidence that they can become dysfunctional in many neurological conditions,” said Mathew Blurton-Jones, UCI professor of neurobiology & behavior and study co-lead author. “Until recently, scientists have mainly been looking at the mechanisms that drive microglial dysfunction and trying to find drugs to change their activity. But with this study, we’ve found a way to potentially harness microglia themselves to treat those diseases.”
Frederick “Chris” Bennett, assistant professor of psychiatry at Penn and co-lead author, added: “There is an obstacle because once our own microglia develop in the location where they are supposed to be in our brains, they don’t give up that space. They block the ability to deliver new cells that would take their place. If you want to insert donor microglia, you have to deplete the host microglia to open up room.”
Bennett and his laboratory partnered with Blurton-Jones and his lab on the project.
Microglia depend on signaling by a protein on their surface called CSF1R for their survival. The FDA-approved cancer drug pexidartinib has been found to block that signaling, killing them. This process would seem to offer a way to clear space in the brain to insert healthy donor microglia. However, there is a dilemma – unless the pexidartinib is stopped before the donor microglia are added, it will eliminate them, too. But once the drug is terminated, the host microglia regenerate too fast to effectively put in the donor cells.
This quandary has challenged efforts to treat people with certain rare and severe neurologic conditions. One is Krabbe disease, in which the body’s cells can’t digest certain fats that are highly abundant in the brain. Currently, clinicians use bone marrow transplantation and chemotherapy to try to introduce new immune cells similar to microglia into the brain. But this approach can be toxic and must be carried out before Krabbe symptoms manifest.
“Our team believed that if we could overcome the brain’s resistance to accepting new microglia, we could successfully transplant them into patients using a safer, more effective process in order to target a great number of diseases,” said co-first author Sonia Lombroso, a Penn Ph.D. student and member of the Bennett Lab. “We decided to investigate whether we could make the donor microglia resistant to the drug that eliminates their host counterparts.”
The researchers used CRISPR gene-editing technology to create one amino acid mutation, known as G795A, which they introduced into donor microglia produced from human stem cells or a mouse microglial cell line. Then they injected the donor microglia into humanized rodent models while administering pexidartinib, with exciting results.
“We discovered that this one small mutation caused the donor microglia to resist the drug and thrive, while the host microglia continued to die off,” said co-first author Jean Paul Chadarevian, a UCI Ph.D. student who is a member of the Blurton-Jones Lab. “This finding could lead to many options for developing new microglial-based treatments. Pexidartinib is already approved for clinical use and appears to be relatively well tolerated by patients.”
Approaches could range from fighting disease by replacing dysfunctional microglia with healthy ones to designing microglia that can recognize imminent threats and strike against them with therapeutic proteins before they cause harm.
The UCI-Penn team believes treatments based on this kind of microglial method could be developed within a decade. Their next investigations include studying in rodent models how to use the approach to attack the brain plaques associated with Alzheimer’s and to counter Krabbe and other similar diseases.
Original Article: Study finds how our brains turn into smarter disease fighters
More from: University of California Irvine | University of Pennsylvania
The Latest Updates from Bing News
Go deeper with Bing News on:
Inserting healthy immune cells into the brain
- 80,000 mouse brain cells used to build a living computer
A computer built using tens of thousands of living brain cells can recognise simple patterns of light and electricity. It could eventually be incorporated into a robot that also uses living muscle ...
- The Importance of the Human Immune System
It recognizes the cells ... brain, bones, and the rest of you well are also good for your immune system: • Eat nutritious foods. • Stay active. • Work to keep your weight healthy.
- Stress-Induced Depression Linked to Immune System Cells
To gain insight into how the alterations ... further understand how γδ T cells in the intestinal immune system may impact the neurological functions in the brain and the role of dectin-1 in ...
- New evidence: immune system cells in the gut linked to stress-induced depression
Targeting changes mediated by these immune ... T cell activity and easing social avoidance behavior. To gain insight into how the alterations in the gut microbiota could impact the human brain ...
- Discovery of an unexpected function of blood immune cells: Their ability to proliferate
In cancer, however, cell proliferation is no longer controlled and becomes chaotic. Researchers have discovered that, in a healthy individual ... form muscles, brain, bones, immune cells, etc.
Go deeper with Bing News on:
Microglial-based treatments
- What You Need to Know About Your Vaginal Microbiome
Last year, the UK-based sustainable tampon brand Daye made headlines for ... of vaginal microorganisms and how they might play a role in the development of treatments for gynecologic conditions. Dr.
- Evidence-Based Treatment Recommendations for Uremic Bleeding
As a result of the complexity of uremic platelet dysfunction and the varying degrees of efficacy of potential treatments, we have proposed an evidence-based management algorithm that can help ...
- Apigenin and Luteolin Modulate Microglial Activation Via Inhibition of STAT1-Induced CD40 Expression
As these compounds have been reported to be potentially cytotoxic, we also examined the level of microglial cell death in response to apigenin and luteolin treatment by LDH assay. [52] We ...
- What Is Tinnitus? Symptoms, Causes And Treatments
Our editorial content is based on thorough research and guidance ... Research has found that this holistic health treatment can be effective for neurological tinnitus. However, just as each ...
- The Best Lice Treatments Of 2023, According To Pediatricians
Our editorial content is based on thorough research and guidance ... read on for the top treatments for children with lice, according to pediatricians on the Forbes Health Advisory Board.
