Spinal microglia replacement delays disease progression and extends survival in a mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder characterized by progressive motor neuron degeneration, leading to paralysis and death typically within 2-5 years of symptom onset. Dysfunctional microglia are strongly implicated in ALS pathogenesis and exhibit dynamic, heterogeneous roles across disease stages. It is thus intriguing whether replacing mutant microglia with normal macrophage-lineage cells could yield therapeutic benefits. Here, using a SOD1G93A mouse model of ALS and a microglia replacement by bone marrow transplantation (Mr BMT) approach, we demonstrated that microglia in the adult spinal cord could be efficiently replaced with bone marrow-derived donor cells. Replacement with non-mutant donor cells in SOD1G93A mice led to reduced microglial activation, delayed symptom progression, and extended survival. Notably, microglia replacement initiated at disease onset achieved survival benefits comparable to presymptomatic intervention. Importantly, the replaced non-mutant cells exhibited neuroprotective transcriptional features and induced remodeling of neuroimmune and glial communication networks. Collectively, our findings suggest that microglia replacement effectively slows ALS progression by correcting mutant microglial dysfunction, offering a promising avenue for ALS treatment.