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While preclinical data has shown that p38\u03b1 inhibition can protect against AD-associated neuropathology, the underlying mechanisms are not fully elucidated. Inhibitors of p38\u03b1 may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to AD pathology. The present study tests this hypothesis by knocking out microglial p38\u03b1 and assessing early-stage pathological changes. Conditional knockout of microglial p38\u03b1 was accomplished in 5-month-old C57BL\/6J wild-type and amyloidogenic AD model (APPswe\/PS1dE9) mice using a tamoxifen-inducible Cre\/loxP system under control of the<jats:italic>Cx3cr1<\/jats:italic>promoter. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field, followed by a later radial arm water maze test and collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included quantification of proinflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics. Loss of microglial p38\u03b1 did not alter behavioral outcomes, proinflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble A\u03b242 and reduce colocalization of Iba1 and 6E10 in a subset of microglia in close proximity to plaques. The data presented here suggest that rather than reducing inflammation<jats:italic>per se<\/jats:italic>, the net effect of microglial p38\u03b1 inhibition in the context of early AD-type amyloid pathology is a subtle alteration of microglia-plaque interactions. Encouragingly from a therapeutic standpoint, these data suggest no detrimental effect of even substantial decreases in microglial p38\u03b1 in this context. Additionally, these results support future investigations of microglial p38\u03b1 signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.<\/jats:p>","DOI":"10.1371\/journal.pone.0286495","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T18:00:54Z","timestamp":1685556054000},"page":"e0286495","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Early chronic suppression of microglial p38\u03b1 in a model of Alzheimer\u2019s disease does not significantly alter amyloid-associated neuropathology"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6967-0489","authenticated-orcid":true,"given":"David 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