A study demonstrates that transplanting human microglia derived from induced pluripotent stem cells (iPSCs) can prevent and reverse neuropathologies in a mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). The research used a chimeric mouse model, hFIRE, which lacks the fms-intronic regulatory element (FIRE) in the CSF1R gene, leading to microglial deficiency and ALSP-like pathologies. Transplantation of human microglia prevented the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. CRISPR-corrected patient-derived iMG also reversed pre-existing pathologies. The study highlights the therapeutic potential of iPSC-derived microglia for ALSP and other microgliopathies. The findings suggest that microglia transplantation could be a promising treatment for ALSP, as it restores a homeostatic microglial state and reduces neuropathologies. The study also shows that microglia engraftment prevents additional ALSP-related pathologies, including brain calcifications, reactive astrocytosis, and microhemorrhages. The results indicate that microglia transplantation could be a viable therapeutic strategy for ALSP and other neurodegenerative diseases. The study also demonstrates that CRISPR correction of ALSP-patient-derived iMG can restore microglial function and reverse pre-existing pathologies. The research provides preclinical evidence supporting the development of microglia transplantation as a potential treatment for ALSP. The study underscores the importance of microglia in maintaining brain health and highlights the potential of iPSC-derived microglia as a therapeutic approach for neurodegenerative diseases.A study demonstrates that transplanting human microglia derived from induced pluripotent stem cells (iPSCs) can prevent and reverse neuropathologies in a mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). The research used a chimeric mouse model, hFIRE, which lacks the fms-intronic regulatory element (FIRE) in the CSF1R gene, leading to microglial deficiency and ALSP-like pathologies. Transplantation of human microglia prevented the development of axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcifications. CRISPR-corrected patient-derived iMG also reversed pre-existing pathologies. The study highlights the therapeutic potential of iPSC-derived microglia for ALSP and other microgliopathies. The findings suggest that microglia transplantation could be a promising treatment for ALSP, as it restores a homeostatic microglial state and reduces neuropathologies. The study also shows that microglia engraftment prevents additional ALSP-related pathologies, including brain calcifications, reactive astrocytosis, and microhemorrhages. The results indicate that microglia transplantation could be a viable therapeutic strategy for ALSP and other neurodegenerative diseases. The study also demonstrates that CRISPR correction of ALSP-patient-derived iMG can restore microglial function and reverse pre-existing pathologies. The research provides preclinical evidence supporting the development of microglia transplantation as a potential treatment for ALSP. The study underscores the importance of microglia in maintaining brain health and highlights the potential of iPSC-derived microglia as a therapeutic approach for neurodegenerative diseases.