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Thus, a model bTNFI, the extracellular domain of type II TNF-\u03b1 receptor (TNFR), which can bind to and sequester TNF-\u03b1, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP\/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Eight-month-old female 3xTg-AD mice were injected intraperitoneally with saline (n\u2009=\u200911) or TfRMAb-TNFR (3\u00a0mg\/kg; n\u2009=\u200911) three days per week for 12\u00a0weeks. Age-matched wild-type (WT) mice (n\u2009=\u20099) were treated similarly with saline. Brains were processed for immunostaining and high-resolution multiplex NanoString GeoMx spatial proteomics.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We observed regional differences in proteins relevant to A\u03b2, tau, and neuroinflammation in the hippocampus of 3xTg-AD mice compared with WT mice<jats:bold>.<\/jats:bold> From 64 target proteins studied using spatial proteomics, a comparison of the A\u03b2-plaque bearing vs. plaque-free regions in the 3xTg-AD mice yielded 39 differentially expressed proteins (DEP) largely related to neuroinflammation (39% of DEP) and A\u03b2 and tau pathology combined (31% of DEP). Hippocampal spatial proteomics revealed that the majority of the proteins modulated by TfRMAb-TNFR in the 3xTg-AD mice were relevant to microglial function (\u2053 33%). TfRMAb-TNFR significantly reduced mature\u00a0A\u03b2 plaques and increased A\u03b2-associated microglia around larger A\u03b2 deposits\u00a0in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature\u00a0A\u03b2\u00a0plaque-associated microglial TREM2 in 3xTg-AD mice.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>Overall, despite the low visual A\u03b2 load in the 11-month-old female 3xTg-AD mice, our results highlight region-specific AD-relevant DEP in the hippocampus of these mice. Chronic TfRMAb-TNFR dosing modulated several DEP involved in AD pathology and showed a largely microglia-centric mechanism of action in the 3xTg-AD mice.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-024-05008-x","type":"journal-article","created":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T11:02:04Z","timestamp":1710759724000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Modulation of hippocampal protein expression by a brain penetrant biologic TNF-\u03b1 inhibitor in the 3xTg Alzheimer\u2019s disease mice"],"prefix":"10.1186","volume":"22","author":[{"given":"Nataraj","family":"Jagadeesan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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