SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain

A role for the trafficking receptor SORLA (Sortilin-related receptor containing LDLR class A repeats) in reducing Aβ 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.