Retromer stabilizing compounds rescue enlarged endosome phenotypes in hiPSC-derived models of AD.

Abstract

The SORL1 gene encodes for the protein SorLA, a sorting receptor involved in retromer-related endosomal traffic. Many SORL1 genetic variants increase Alzheimer's disease (AD) risk, and rare loss-of-function truncation mutations have been found to be causal of AD. Previous work has shown that SORL1 depletion results in enlarged early endosomes in hiPSC-derived neurons. We used CRISPR/Cas9 technology to insert SORL1 AD-risk variants in human induced pluripotent stem cells (hiPSCs) to test the hypothesis that risk variants in the VPS10 domain of SORL1 (SORL1 VPS10 variants) contribute to AD pathogenesis by leading to dysfunction in endosomal trafficking. We report that SORL1 VPS10 variants in hiPSC-derived neurons lead to early endosome enlargement, a cellular phenotype that is indicative of 'traffic jams' and is now considered a hallmark cytopathology AD. We determine that the retromer stabilizing compound TPT-260 reduces early endosome enlargement in SORL1 VPS10 variants. Our data, together with recent findings, underscores how sporadic AD pathways that regulate endosomal trafficking, and autosomal-dominant AD pathways that regulate APP cleavage, independently converge on AD's defining cytopathology. Moreover, demonstrating a partial rescue of cellular phenotypes in SORL1 VPS10 variants will contribute to the development of new and precision treatments for AD.