ABOVE: Image of brain cells showing pyramidal neurons in green, astrocytes in red, and microglia in blue © ISTOCK.COM, SELVANEGRA
Some of today’s most cutting-edge treatments, from immunotherapy to gene editing, are based on the principle of swapping in more-functional versions of certain cell types or the genes within them. Now, in a study published yesterday (March 16) in Science Translational Medicine, researchers report they’ve achieved this in the mouse brain, clearing out a critical population of immune cells known as microglia and replacing them with new ones. Moreover, they say, this procedure led to an improvement in symptoms for mice with a neurodegenerative disease linked to microglial malfunction.
Though they’ve long received less attention than neurons, microglia play important roles in the brain, including clearing dead cells and defective proteins as well as shaping the formation of memories. Dysfunctional microglia have been linked to neurodegenerative diseases such as Alzheimer’s, making them an attractive therapeutic target.
See “Microglia as Therapeutic Targets in Neurodegenerative Diseases”
In the new study, researchers set out to try to replace microglia. Some types of immune cells can be replaced via a bone marrow transplant, since cells within the bone marrow pump immune cells into the blood. But the team found that microglia were different—too entrenched in the brain to be displaced by newcomers. So the group tried a treatment coupling bone marrow transplants with a chemical that killed existing microglia, and found that this allowed new microglia to take hold. However, the replacements behaved differently in subtle ways than the cells they replaced, the researchers report—for example, more actively clearing cellular debris.
The researchers then tested whether this replacement technique could make a difference to a condition involving microglia. They used mice with a neurodegenerative disease caused by low levels of a protein called prosaposin in their microglia and other cells, and found that replacing their microglia via transplants from mice without the condition improved the animals’ movement and lifespans.
“Essentially, any genetic disease that affects microglia would be a fantastic target,” coauthor Marius Wernig of Stanford University tells STAT. “Because in this case, you know that you fixed the problem.”
“Definitely interesting, and maybe, potentially translationally relevant,” immunologist Susan Kaech of the Salk Institute who was not involved in the study tells the publication.
Wernig’s team plans to test the procedure in monkeys, STAT reports, and is seeking a way to make the protocol less toxic. The group also plans to analyze whether the differences they found between the old and new microglia could affect their function.