Depletion of the AD risk gene SORL1 causes endo‐lysosomal dysfunction in human microglia

Alzheimer’s disease (AD) is a neurodegenerative disorder which is currently incurable. Prior to well‐established neuropathological changes in AD, enlarged early endosomes are cytopathological hallmark of AD and strong genetic evidence links genes involved in intra‐cellular trafficking, mediated by endo‐lysosomal pathway, to increased AD risk, suggesting that this pathway is integral to the pathogenesis of AD. We recently identified SORL1, an intracellular sorting receptor as a potential regulator of this pathway. Using CRISPR/Cas9 to deplete SORL1 in human induced pluripotent stem cells (hiPSCs), we showed that loss of SORL1 results in enlarged early endosomes in (hiPSCs)‐derived neurons, but not microglia. This model replicates the earliest AD cytopathology and our data underscores important cell‐type specific differences in response to loss of SORL1. Building on this study, we further examined alterations in lysosomal function, with altered expression of SORL1 in hiPSC‐derived microglia.