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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • CRISPR-Cas Systems / genetics
  • Cell Differentiation
  • Cell Line
  • Endosomes / metabolism*
  • Gene Editing
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • LDL-Receptor Related Proteins / antagonists & inhibitors
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Transport
  • RNA Interference
  • RNA, Guide, CRISPR-Cas Systems / metabolism
  • RNA, Small Interfering / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • LDL-Receptor Related Proteins
  • Membrane Transport Proteins
  • RNA, Guide, CRISPR-Cas Systems
  • RNA, Small Interfering
  • SORL1 protein, human
  • Amyloid Precursor Protein Secretases