Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R+/- mouse model of ALSP, which can be rescued via CSF1R inhibitors

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant neurodegenerative disease caused by mutations in colony-stimulating factor 1 receptor (CSF1R). We sought to identify the role of microglial CSF1R haploinsufficiency in mediating pathogenesis. Using an inducible Cx3cr1(CreERT2/+)-Csf1r(+/fl) system, we found that postdevelopmental, microglia-specific Csf1r haploinsufficiency resulted in reduced expression of homeostatic microglial markers. This was associated with loss of presynaptic surrogates and the extracellular matrix (ECM) structure perineuronal nets. Similar phenotypes were observed in constitutive global Csf1r haplo-insufficient mice and could be reversed/prevented by microglia elimination in adulthood. As microglial elimination is unlikely to be clinically feasible for extended durations, we treated adult CSF1R(+/-) mice at different disease stages with a microglia-modulating dose of the CSF1R inhibitor PLX5622, which prevented microglial dyshomeostasis along with synaptic- and ECM-related deficits. These data highlight microglial dyshomeostasis as a driver of pathogenesis and show that CSF1R inhibition can mitigate these phenotypes.

Automated summary

The study showed that microglial CSF1R haploinsufficiency leads to microglial dysregulation, characterized by reduced expression of cellular markers, and synaptic and extracellular matrix deficits. Treatment with a CSF1R inhibitor prevented these abnormalities, highlighting the potential therapeutic benefit of targeting CSF1R in mitigating the pathogenesis of the disease.