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

## TL;DR

Researchers show that a microglia replacement strategy can reduce brain damage in a mouse model of a genetic disorder affecting microglia.

## Contribution

A novel microglia replacement strategy called DCMDT is proposed as a potential treatment for microgliopathy.

## Key findings

- Csf1rI792T/+ mice show cognitive deficits and brain pathology similar to human CSF1R-related disorder.
- Csf1rI792T/+ microglia display an activated disease-associated microglia (DAM)-like phenotype.
- The DCMDT strategy significantly reduces neuropathological deficits in the mouse model.

## Abstract

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.

•CSF1R p.I794T is a global hotspot mutation underlying CSF1R-RD•Csf1rI792T/+ mice recapitulate key clinical and pathological features of CSF1R-RD•Csf1rI792T/+ microglia exhibit an activated and DAM-like phenotype•A microglial replacement strategy attenuates the deficits in Csf1rI792T/+ mice

CSF1R p.I794T is a global hotspot mutation underlying CSF1R-RD

Csf1rI792T/+ mice recapitulate key clinical and pathological features of CSF1R-RD

Csf1rI792T/+ microglia exhibit an activated and DAM-like phenotype

A microglial replacement strategy attenuates the deficits in Csf1rI792T/+ mice

Li et al. define the clinical features of patients carrying the CSF1R p.I794T variant and establish a corresponding knockin mouse model. They show that Csf1rI792T/+ microglia adopt a disease-associated state and that a microglial replacement strategy, DCMDT, mitigates cognitive and neuropathological deficits in CSF1R-related disorder.