SORL1 regulates tau trafficking

Background While LRP1 is a cellular receptor that mediates tau uptake and potentiates tau seeding, we observed LRP1‐independent uptake of tau in LRP1‐genetically deficient cells and hypothesized that the sortilin‐related receptor (SORL1) could also be involved in tau processing. Method Surface plasmon resonance was used to assess tau binding to SORL1. 125I‐labelled tau uptake assays were used to investigate the role of SORL1 in endocytosis. The P301S FRET biosensor was used to assess SORL1’s role in cytosolic tau seeding, using both WT and AD‐associated mutations in the SORL1 gene (G511R and N1358S). Confocal microscopy was used to investigate colocalization and intracellular trafficking of tau and SORL1. Finally, we investigated the impact of SORL1 on tau processing in vivo by injecting human pathogenic tau isolated from AD patients into the hippocampus of SORL1 knockout vs wildtype mice and analyzing via immunohistochemistry. Result We confirmed high‐affinity binding of tau to SORL1 and found that fluorescently labeled tau colocalizes with overexpressed SORL1 in H4 neuroglioma cells. When we knocked down SORL1 expression using siRNA in H4 cells, we observed a significant increase in the LRP1‐mediated degradation of 125I‐labeled tau, revealing that SORL1 directs tau away from lysosomal degradative pathways. To determine if this occurs in vivo, we injected pathogenic forms of human tau into the hippocampal region of WT and SORL1‐deficient mice. Two days following injection, preliminary results suggest less human tau retention in the brains of SORL1‐deficient mice when compared to WT controls. Together, these data suggest that SORL1 may have a dual function in tau metabolism: impacting both uptake of tau, and trafficking of pathogenic tau to lysosomes. We also found that SORL1 promotes cytosolic tau seeding induced by pathogenic forms of tau. The AD‐associated N1358S mutation SORL1 gene demonstrated a significant increase in tau seeding when compared with WT SORL1. Conclusion These studies identify SORL1 as a sorting receptor for tau that contributes to seeding of pathogenic tau. Furthermore, they indicated that SORL1 directs tau away from lysosomal degradation pathways, and identify promotion of tau seeding as a potential mechanism by which the SORL1 N1358S mutation contributes to AD.