A strategy of microglia replacement alleviates microgliopathy in a CSF1R I794T hotspot mutation mouse model of CSF1R-related disorder

The I794T hotspot mutation in the colony-stimulating factor 1 receptor (CSF1R) gene is associated with primary microgliopathy manifesting as leukoencephalopathy. In this study, we identify three Chinese probands harboring the CSF1R p.I794T variant and characterize their clinical and neuroimaging profiles. To elucidate disease mechanisms and explore therapeutic avenues, we generate a Csf1rI792T/+ knockin mouse model that carries this human mutation. These Csf1rI792T/+ mice exhibit hallmark features of CSF1R-related disorder (CSF1R-RD), including cognitive deficits, ventricular enlargement, reduced microglia, axonal spheroids, and demyelination. Transcriptomic analysis reveals that Csf1rI792T/+ microglia adopt an activated and disease-associated microglia (DAM)-like phenotype. Crucially, we develop and test a microglia replacement strategy, termed "duplicate-cyclic microglial depletion for transplantation" (DCMDT), which significantly ameliorates neuropathological deficits in Csf1rI792T/+ mice. Our findings highlight the pathological significance of the CSF1R p.I794T mutation and propose DCMDT as a promising therapeutic approach for neurodegenerative disorders driven by microglial dysfunction.