Familial Alzheimer disease mutation identifies novel role of SORLA in release of neurotrophic exosomes

Sortilin-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs target proteins between endocytic and secretory compartments of cells. Mutations in SORL1, encoding SORLA, are common in individuals suffering from Alzheimer disease (AD) of unknown etiology. Conceptually, characterization of inheritable SORL1 variants associated with AD can provide important new information about functions of this receptor relevant for aging brain health. Here, we focused on elucidation of the AD-associated variant SORLA N1358S, carrying a mutation in the main ligand binding domain of the receptor. Using unbiased quantitative proteome screens, we identified major alterations in the mutant receptor interactome linked to biogenesis and secretion of exosomes. Using advanced biophysical, cell biological, as well as functional studies in stem cell-derived human cell models we corroborated impaired release and loss of neurotrophic action of exosomes from neurons and microglia expressing SORLAN1358S. An impaired neurotrophic potential was attributed to an altered exosomal content of RNA binding proteins and associated microRNAs, known to control neuronal growth and maturation. Our studies identified a so far unknown function for SORLA in controlling the quantity and trophic quality of extracellular vesicles secreted by cells, and they argue for impaired cellular cross talk through exosomes as a pathological trail contributing to the risk of AD seen with carriers of SORL1 variants.