SORL1 is a receptor for tau that promotes tau seeding

Joanna M Cooper; Aurelien Lathuiliere; Enming J Su; Yuyu Song; Daniel Torrente; Youhwa Jo; Nicholas Weinrich; Jennifer Diaz Sales; Mary Migliorini; Thomas H Sisson; Daniel A Lawrence; Bradley T Hyman; Dudley K Strickland

doi:10.1016/j.jbc.2024.107313

SORL1 is a receptor for tau that promotes tau seeding

J Biol Chem. 2024 Apr 22:107313. doi: 10.1016/j.jbc.2024.107313. Online ahead of print.

Affiliations

¹ The Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201.
² Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA; Memory Center, Department of Rehabilitation and Geriatrics, Geneva University Hospital and University of Geneva, Geneva, Switzerland.
³ Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI.
⁴ Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.
⁵ Patricia and John Rosenwald Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY.
⁶ Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA. Electronic address: bhyman@mgh.harvard.edu.
⁷ The Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201; Departments of Physiology and University of Maryland School of Medicine, Baltimore, MD 21201; Departments of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201. Electronic address: dstrickland@som.umaryland.edu.

PMID: 38657864
DOI: 10.1016/j.jbc.2024.107313

Abstract

Sortilin-related receptor 1 (SORL1) is an intracellular sorting receptor genetically implicated in Alzheimer's disease (AD) that impacts amyloid precursor protein trafficking. The objective of these studies was to test the hypothesis that SORL1 binds tau, modulates its cellular trafficking and impacts the aggregation of cytoplasmic tau induced by pathological forms of tau. Using surface plasmon resonance measurements, we observed high-affinity binding of tau to SORL1 and the vacuolar protein sorting 10 (VPS10) domain of SORL1. Interestingly, unlike LRP1, SORL1 binds tau at both pH 7.4 and pH 5.5, revealing its ability to bind tau at endosomal pH. Immunofluorescence studies confirmed that exogenously added tau colocalized with SORL1 in H4 neuroglioma cells, while overexpression of SORL1 in LRP1-deficient Chinese hamster ovary (CHO) cells resulted in a marked increase in the internalization of tau, indicating that SORL1 can bind and mediate the internalization of monomeric forms of tau. We further demonstrated that SORL1 mediates tau seeding when tau RD P301S FRET biosensor cells expressing SORL1 were incubated with high molecular weight forms of tau isolated from the brains of patients with AD. Seeding in H4 neuroglioma cells is significantly reduced when SORL1 is knocked down with siRNA. Finally, we demonstrate that the N1358S mutant of SORL1 significantly increases tau seeding when compared to WT SORL1, identifying for the first time a potential mechanism that connects this specific SORL1 mutation to Alzheimer's disease. Together, these studies identify SORL1 as a receptor that contributes to trafficking and seeding of pathogenic tau.

Keywords: SORL1; Tau protein (Tau); apolipoprotein E (ApoE); lipoprotein receptor-related protein (LRP); neurodegenerative disease; tau seeding; tauopathy.