HMN 2025: How Can immune cells stave off devastating neurodegenerative diseases? Scientists aim to find out

An evolving form of therapy to treat devastating neurodegenerative disorders by injecting fresh immune cells—microglia—directly into the brain, promises a new lease on health by slowing the progression of mind-robbing conditions.

The research, underway in China, is in the pre-clinical phase of investigation and is aimed at protecting vital neurons, while at the same time, combating the early hallmarks of neurological disorders, such as Alzheimer’s disease.

So far, the microglia transplants have been performed in animal models, but they have ameliorated symptoms of neurological disease.

Microglia are highly dynamic cells, constantly extending and retracting their antennae-like extensions to scrutinize the brain’s complete environment, performing crucial immune surveillance and tissue repair. In short, these cells are on the job around the clock, searching for threats both subtle and overt.

The new research is reported in the journal Science Translational Medicine and is led by a team of investigators at the Institute of Neuroscience in the School of Medicine at Xiamen University in Fujian Province. The Xiamen team is one of several throughout China participating in the study.

Scientists who are working on the new strategy to replenish microglial cells in the brain report that theirs is an update on another technique from the past. The difference is that the investigational approach offers a new and improved method to slow the loss of neurons and abate the progression of numerous neurodegenerative diseases.

“Genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy,” writes Dr. Dadian Chen, lead author of the study.

Chen and colleagues theorize that replacing dysfunctional microglia can help treat a range of neurologic disorders. However, traditional methods to replenish microglia rely on bone marrow transplantation, which has proven arduous and inefficient.

Moreover, bone marrow transplants require strict preconditioning regimens that use radiation or chemotherapy, which can damage the brain, and the microglia that result from the transplanted bone marrow aren’t faithful copies of the originals, Chen and collaborators say.

“Traditional bone marrow transplantation methods for replenishing brain microglia have limitations,” continued Chen, who noted that the risks associated with these methods can sometimes outweigh the benefits. Problems may include low microglial cell efficiency and the potential for brain injury because of preconditioning regimens, such as radiation or chemotherapy.

“Bone marrow transplantation (hematopoietic stem cell transplantation) is a widely used cell therapy method for hematological malignancies,” Chen added. “This procedure requires conditioning through irradiation or chemotherapy to eliminate the recipient’s bone marrow, creating a receptive environment for donor stem cell engraftment.”

Given that bone marrow-derived cells can partially replace microglia in the brain, Chen further explained in the study that attempts have been made to treat certain conditions, such as leukodystrophies and lysosomal storage disorders, with bone marrow transplants to boost microglial cells. The efforts have not always been successful.

To avoid the need for radiation or chemo, Chen and colleagues developed a new approach called tricyclic microglial depletion for transplantation. The multi-pronged approach involved depleting the native, dysfunctional microglia and allowed cultured, healthy versions of the cells to flourish in the brains of mice bred to develop specific human neurodegenerative diseases. Microglial cells were injected into the cortex and hippocampus brain regions of the animals.

The treatment strategy used three cycles of an experimental compound, PLX3397, which inhibits the CSF1R receptor located on the surface of the immune cells known as macrophages. Inhibition of the receptor allows the new microglia to proliferate.

Also known as resident macrophages, microglia inhabit the central nervous system, and are highly specialized warriors that fight infection, cancer and other threats that can invade the brain. Unlike other brain cells, microglia are of hematopoietic origin, meaning they originate from blood-forming cells. Transplanting them directly into the brain may stave off the onset of aberrant conditions, Chen and colleagues say.

In the study, transplanted microglia sufficiently engrafted into mouse-model brains and acquired properties similar to the animals’ endogenous microglia.

Proof-of-concept experiments in humanized mouse models suggest that microglia replacement can alleviate pathology associated with microglia dysfunction. The microglial cells used in the experiments were derived from neonatal mice.

Chen, and a team of collaborators from throughout China, found that when given before symptoms emerged, the transplants replaced defective microglia and slowed the degeneration of neurons in mouse models of both Alzheimer’s disease and Sandhoff disease, an inherited neurodegenerative disorder.

The team is calling for further research into the biological mechanisms that allow the microglia to engraft. The scientists also want to test whether human-induced pluripotent stem cells can be used as a more clinically relevant source for microglia.

“The long-term safety and efficacy of the tricyclic microglial depletion for transplantation approach needs to be thoroughly evaluated in preclinical models,” Chen wrote in conclusion, but acknowledged that the future appears bright for the transplant methodology. “Although our results are promising, several questions remain to be addressed in future studies.

“Our findings highlight the tricyclic microglial depletion for transplantation strategy as a practical, innovative, and potentially translatable approach for treating a wide range of neurological disorders associated with microglial dysfunction.”

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