Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s gene SORL1

The Sortilin-related receptor 1 gene ( SORL1, SORLA) is strongly associated with risk of developing Alzheimer’s disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a ‘master conductor’ of endosomal trafficking. Pharmacological chaperones stabilize retromer in vitro , enhancing its function. Here we used an isogenic series of human induced pluripotent stem cell (hiPSC) lines with either one or two copies of SORL1 or harboring one copy of a SORL1 variant linked to increased risk for AD. We treated hiPSC-derived cortical neurons with the established retromer chaperone, TPT-260, and tested whether indicators of AD’s defining endosomal, amyloid, and Tau pathologies were corrected. We observed that the degree of rescue by TPT-260 treatment varied, depending on the number of copies of functional SORL1 and which SORL1 variant was expressed. Using a disease-relevant preclinical model, our work illuminates how the SORL1 -retromer pathway can be therapeutically harnessed. ### Competing Interest Statement The authors have declared no competing interest.