Pharmacologic Stabilization of Retromer Rescues Endosomal Pathology Induced by Defects in the Alzheimer’s Genesorl1
Alzheimer's & dementia(2022)
Abstract
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.
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