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Adv."],"published-print":{"date-parts":[[2026,7,17]]},"abstract":"<jats:p>A role for the trafficking receptor SORLA (Sortilin-related receptor containing LDLR class A repeats) in reducing A\u03b2 levels has been well established; however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo. Here, we show that transgenic SORLA up-regulation (SORLA TG) can attenuate pathological effects in aged PS19 (P301S tau) mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, long-term potentiation (LTP) impairment, and glial hyperactivation. Proteomic analysis indicates attenuation of PS19 profiles in PS19\/SORLA TG hippocampus, including pathological changes in synapse-related proteins and key drivers of synaptic dysfunction such as ApoE and C1q. Single-nucleus RNA sequencing analysis reveals suppression of PS19 signatures with SORLA up-regulation and identifies a previously unrecognized involvement of Sema4D-PlexinB1\/B2 signaling in glial pathology. In contrast, SORLA deletion exacerbates tau seeding and aggregation, glial hyperactivation, and PlxnB1\/B2 induction in PS19 hippocampus. These results indicate that SORLA confers neuroprotection against tau toxicity in the PS19 mouse brain.<\/jats:p>","DOI":"10.1126\/sciadv.aed6825","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:58:48Z","timestamp":1784311128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2471-8351","authenticated-orcid":true,"given":"Huijie","family":"Huang","sequence":"first","affiliation":[{"name":"Center for Neurologic Diseases, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Huan","family":"Shi","sequence":"additional","affiliation":[{"name":"Center for Data Sciences, Sanford Burnham Prebys Medical Discovery 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