A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ

Neuron. 2019 Oct 23;104(2):256-270.e5. doi: 10.1016/j.neuron.2019.07.010. Epub 2019 Aug 12.


Familial Alzheimer's disease (fAD) results from mutations in the amyloid precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes. Here we leveraged recent advances in induced pluripotent stem cell (iPSC) and CRISPR/Cas9 genome editing technologies to generate a panel of isogenic knockin human iPSC lines carrying APP and/or PSEN1 mutations. Global transcriptomic and translatomic profiling revealed that fAD mutations have overlapping effects on the expression of AD-related and endocytosis-associated genes. Mutant neurons also increased Rab5+ early endosome size. APP and PSEN1 mutations had discordant effects on Aβ production but similar effects on APP β C-terminal fragments (β-CTFs), which accumulate in all mutant neurons. Importantly, endosomal dysfunction correlated with accumulation of β-CTFs, not Aβ, and could be rescued by pharmacological modulation of β-secretase (BACE). These data display the utility of our mutant iPSCs in studying AD-related phenotypes in a non-overexpression human-based system and support mounting evidence that β-CTF may be critical in AD pathogenesis.

Keywords: Alzheimer’s disease; Aβ; CRISPR/Cas9; Rab5; amyloid precursor protein; amyloid-beta; beta-C-terminal fragment; endocytosis; induced pluripotent stem cell; presenilin; β-CTF.

Publication types

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

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / genetics*
  • Aspartic Acid Endopeptidases
  • CRISPR-Cas Systems
  • Cell Line
  • Endocytosis / genetics*
  • Endosomes / metabolism*
  • Endosomes / pathology
  • Gene Expression Profiling
  • Gene Knock-In Techniques
  • Heterozygote
  • Homozygote
  • Humans
  • Induced Pluripotent Stem Cells
  • Mutation
  • Neurons / metabolism*
  • Organelle Size
  • Peptide Fragments / metabolism*
  • Phenotype
  • Presenilin-1 / genetics*
  • Proteomics
  • rab5 GTP-Binding Proteins / metabolism


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-42)
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • RAB5C protein, human
  • rab5 GTP-Binding Proteins