Familial Alzheimer disease mutation in SORL1 impairs release of neurotrophic extracellular vesicles by microglia

Coding mutations in SORL1, the gene encoding sortilin-related receptor with A-type repeats (SORLA) are common in individuals suffering from Alzheimer’s disease (AD) of unknown etiology. These findings suggest SORL1 as a novel familial disease gene causative of AD. SORL1 mutations characterized so far have mainly been shown to impact folding and maturation of the receptor polypeptide. While these previous findings support the relevance of SORLA dysfunction for AD pathology, they provide little information about activity of this intracellular sorting receptor crucial for aging brain health. Here, we have characterized the N1358S variant of SORLA, carrying a mutation in a major ligand binding domain of the receptor. Using unbiased interactome studies, we show that N1358S impacts the ability of SORLA to interact with proteins involved in formation and release of extracellular vesicle (EVs) from cells. Consequently, expression of SORLAN1358S in iPSC-derived human microglia impairs their ability to produce trophic EVs that support maturation of neurons, a defect also seen in microglia lacking the receptor. Our findings document a unique role for SORLA in microglia to neuron crosstalk through EVs, and suggest loss of neurotrophic support in the brain of SORL1N1358S carriers.