{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:12:30Z","timestamp":1793329950187,"version":"4.5.0"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"796","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,4,30]]},"abstract":"<jats:p>\n                    Growing genetic and pathological evidence has identified microglial dysfunction as a key contributor to the pathogenesis and progression of various neurological disorders, positioning microglia replacement as a promising therapeutic strategy. Traditional bone marrow transplantation (BMT) methods for replenishing brain microglia have limitations, including low efficiency and the potential for brain injury because of preconditioning regimens, such as irradiation or chemotherapy. Moreover, BM-derived cells that migrate to the brain do not recapitulate the phenotypic and functional properties of resident microglia. Here, we present a microglia transplantation strategy devoid of any conditioning, termed \u201ctricyclic microglial depletion for transplantation\u201d (TCMDT). This approach leverages three cycles of microglial depletion using the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, creating an optimal window for efficient engraftment of exogenous microglia. Transplantation of primary cultured microglia by TCMDT successfully restored the identity and functions of endogenous microglia. To evaluate the therapeutic potential of TCMDT, we applied this strategy to two distinct mouse models of neurologic disorder. In a Sandhoff disease model, a neurodegenerative lysosomal storage disorder caused by hexosaminidase subunit beta (\n                    <jats:italic toggle=\"yes\">Hexb<\/jats:italic>\n                    ) deficiency, TCMDT effectively replaced deficient microglia, attenuating neurodegeneration and improving motor performance. Similarly, in an Alzheimer\u2019s disease (AD)\u2013related amyloid mouse model carrying the triggering receptor expressed on myeloid cells 2 (Trem2) R47H mutation, our transplantation strategy rescued microglial dysfunction and mitigated AD-related pathology. Overall, our study introduces TCMDT as a practical, efficient, and safe approach for microglia replacement, suggesting therapeutic potential for treating neurological disorders associated with microglial dysfunction.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ads6111","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T22:02:49Z","timestamp":1746050569000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":41,"title":["Brain-wide microglia replacement using a nonconditioning strategy ameliorates pathology in mouse models of neurological disorders"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9773-7123","authenticated-orcid":true,"given":"Dadian","family":"Chen","sequence":"first","affiliation":[{"name":"Xiamen Key Laboratory of Brain Center, First Affiliated Hospital of Xiamen University and Fujian Provincial Key Laboratory of 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