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Prior investigations reported that the elimination of ~80% of microglia through inhibition of the colony\u2010stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the effects of short\u2010term CSF1R inhibition during the early stages of neuroinflammation on residual microglia are unknown. Therefore, we investigated the effects of 10\u2010day CSF1R inhibition using PLX5622 in three\u2010month\u2010old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal A\u03b2 plaques. We observed ~65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia displayed a noninflammatory phenotype with reduced NOD\u2010, LRR\u2010, and pyrin domain\u2010containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque\u2010associated microglia were reduced with diminished Clec7a expression. Additionally, phosphorylated S6 ribosomal protein and the protein sequestosome 1 analysis suggested reduced mechanistic targets of rapamycin (mTOR) signaling and autophagy in microglia and neurons within the hippocampus and cerebral cortex. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling in the hippocampus and cerebral cortex, and enhanced autophagy in the hippocampus. However, short\u2010term CSF1R inhibition did not influence A\u03b2 plaques, soluble A\u03b2\u201042 levels, astrocyte hypertrophy, or hippocampal neurogenesis. Thus, short\u2010term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.<\/jats:p>","DOI":"10.1111\/acel.14398","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T17:40:29Z","timestamp":1732210829000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Residual microglia following short\u2010term PLX5622 treatment in 5xFAD mice exhibit diminished NLRP3 inflammasome and mTOR signaling, and enhanced autophagy"],"prefix":"10.1111","volume":"24","author":[{"given":"Maheedhar","family":"Kodali","sequence":"first","affiliation":[{"name":"Institute for Regenerative Medicine, Department of Cell Biology and Genetics Texas A&amp;M University Health Science Center School of Medicine  College Station Texas 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