Microglia replacement halts rare brain disease progression

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a fatal brain disease caused by a mutation in one copy of the gene encoding colony-stimulating factor 1 receptor (CSF1R), which is mainly expressed in microglia. However, little is known about the pathology owing to a lack of appropriate mouse models. In a paper in Science, Wu et al. introduce two mouse models harboring hotspot mutations in human CSF1R that closely mimic the ALSP phenotype, with fewer microglia, brain calcification, myelin pathology, axonal swelling and spheroids. They then explored whether replacing mutated microglia with healthy ones could be an effective treatment strategy.

The authors first tested a previously developed strategy that depleted microglia through CSF1R inhibition and then replaced them via bone marrow transplantation. This treatment rescued neural signal transduction and improved cognitive and motor function. In the case of CSF1R-deficient microglia in ALSP, the authors reasoned that microglia depletion might not be necessary. Indeed, a traditional bone marrow transplant had similar therapeutic effects.

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