Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing
Allison Knupp,
Swati Mishra,
Refugio Martinez,
Jacquelyn E. Braggin,
Marcell Szabo,
Chizuru Kinoshita,
Dale W. Hailey,
Scott A. Small,
Suman Jayadev,
Jessica E. Young
Affiliations
Allison Knupp
Department of Pathology, University of Washington, Seattle, WA 98109, USA
Swati Mishra
Department of Pathology, University of Washington, Seattle, WA 98109, USA
Refugio Martinez
Department of Pathology, University of Washington, Seattle, WA 98109, USA
Jacquelyn E. Braggin
Department of Neurology, University of Washington, Seattle, WA 98195, USA
Marcell Szabo
Department of Pathology, University of Washington, Seattle, WA 98109, USA
Chizuru Kinoshita
Department of Pathology, University of Washington, Seattle, WA 98109, USA
Dale W. Hailey
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
Scott A. Small
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY 10032, USA
Suman Jayadev
Department of Neurology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA
Jessica E. Young
Department of Pathology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Corresponding author
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.
