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

Abstract

AbstractBackgroundDefects in the Sortilin‐related receptor 1 gene, SORL1, are highly pathogenic Alzheimer’s disease (AD), on par with other causal AD genes. SORL1 is a key regulator of endosomal trafficking in neurons, and loss of SORL1 function disrupts trafficking pathways that are vital for neuronal health. SORL1 has been found to interact with retromer, a trafficking complex that is a ‘master conductor’ of endosomal outflow. Here we rely on retromer pharmacological chaperones that stabilize retromer in vitro, and thus enhance retromer function in cells to test the hypothesis that they will correct AD‐associated neuronal pathologies.MethodWe used an isogenic series of human induced pluripotent cell lines either deficient in SORL1 expression (SORL1 KO or SORL1+/−) or harboring a one copy of a missense variant linked to increased risk for AD (SORL1Var). We treated neurons derived from these hiPSCs with the established retromer chaperone, TPT‐260, and tested whether they corrected indicators of AD’s defining endosomal, amyloid, and tau pathologies.ResultWe observed that TPT‐260 treatment was able to correct all of these pathological indicators, however the degree of rescue of some of the phenotypes was dependent one whether the neurons harbor at least one functional copy of SORL1 or whether they are fully deficient.ConclusionMore than just validating that SORL1‐retromer acts a trafficking functional unit in neurons, our work sheds new light on how SORL1‐retromer is linked to AD’s cardinal pathologies and illuminates how this pathway can be therapeutically harnessed.