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

  • Cell Rep. 2020 Jun 2;31(9):107719. doi: 10.1016/j.celrep.2020.107719.
Allison Knupp  1 ,  Swati Mishra  1 ,  Refugio Martinez  1 ,  Jacquelyn E Braggin  2 ,  Marcell Szabo  1 ,  Chizuru Kinoshita  1 ,  Dale W Hailey  3 ,  Scott A Small  4 ,  Suman Jayadev  5 ,  Jessica E Young  6
Affiliations
  • 1. Department of Pathology, University of Washington, Seattle, WA 98109, USA.
  • 2. Department of Neurology, University of Washington, Seattle, WA 98195, USA.
  • 3. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
  • 4. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University, New York, NY 10032, USA.
  • 5. Department of Neurology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA.
  • 6. Department of Pathology, University of Washington, Seattle, WA 98109, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: [email protected].
PMID: 32492427 DOI: 10.1016/j.celrep.2020.107719
Abstract

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.

Keywords
Alzheimer's disease; SORL1; early endosomes; human induced pluripotent stem cells.
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