2. Academic Validation
  3. Depletion of the AD Risk Gene SORL1 Selectively Impairs Neuronal Endosomal Traffic Independent of Amyloidogenic APP Processing

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

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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