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Here, we generated immunoproteasome-deficient PS19 tauopathy and APP\/human tau double-knock-in mice by crossing each disease model with L7M1 mice lacking two immunoproteasome catalytic subunits. Immunoproteasome deficiency increased phospho-tau burden, exacerbated amyloid-\u03b2 pathology and heightened microglial reactivity without suppressing constitutive 26S proteasome activity. In primary microglia and longitudinal two-photon imaging, immunoproteasome-deficient microglia engaged and engulfed tau aggregate\u2013bearing material but failed to resolve internalized cargo, revealing a post-engulfment degradative checkpoint. Single-nucleus transcriptomics identified a remodeled P2ry12\n                  <jats:sup>low<\/jats:sup>\n                  \/Trem2\n                  <jats:sup>high<\/jats:sup>\n                  microglial state with impaired phagolysosomal and mitochondrial programs. Reanalysis of human single-nucleus transcriptomic datasets showed that reduced microglial immunoproteasome expression was associated with cargo-processing gene-program changes similar to those observed in immunoproteasome-deficient mouse microglia. Together, these findings identify immunoproteasome biogenesis as a protective glial stress response that supports microglial aggregate clearance in AD.\n                <\/jats:p>","DOI":"10.64898\/2026.07.14.738427","type":"posted-content","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T19:50:13Z","timestamp":1784577013000},"source":"Crossref","is-referenced-by-count":0,"title":["Immunoproteasome Deficiency Impairs Microglial Clearance and Worsens Tau and Amyloid Pathology"],"prefix":"10.64898","author":[{"given":"Malavika","family":"Srikanth","sequence":"first","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center. New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center. New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Wellman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrita","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center. New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella E.","family":"Lorman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center. New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Lantin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Columbia University. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avery M.","family":"Runyan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center. New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center. New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayank","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center. 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