Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing

• Main Authors: Allison Knupp, Swati Mishra, Refugio Martinez, Jacquelyn E. Braggin, Marcell Szabo, Chizuru Kinoshita, Dale W. Hailey, Scott A. Small, Suman Jayadev, Jessica E. Young
• Format: Article
• Language: English
• Published: Elsevier 2020-06-01
• Series: Cell Reports
• Subjects: Alzheimer's disease; human induced pluripotent stem cells; SORL1; early endosomes
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720306963

Summary: SORL1/SORLA is a sorting receptor involved in retromer-related endosomal traffic and an Alzheimer’s disease (AD) risk gene. Using CRISPR-Cas9, we deplete SORL1 in hiPSCs to ask if loss of SORL1 contributes to AD pathogenesis by endosome dysfunction. SORL1-deficient hiPSC neurons show early endosome enlargement, a hallmark cytopathology of AD. There is no effect of SORL1 depletion on endosome size in hiPSC microglia, suggesting a selective effect on neuronal endosomal trafficking. We validate defects in neuronal endosomal traffic by showing altered localization of amyloid precursor protein (APP) in early endosomes, a site of APP cleavage by the β-secretase (BACE). Inhibition of BACE does not rescue endosome enlargement in SORL1-deficient neurons, suggesting that this phenotype is independent of amyloidogenic APP processing. Our data, together with recent findings, underscore how sporadic AD pathways regulating endosomal trafficking and autosomal-dominant AD pathways regulating APP cleavage independently converge on the defining cytopathology of AD.