Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons With Familial Alzheimer's Disease Mutations

Cell Rep. 2016 Oct 11;17(3):759-773. doi: 10.1016/j.celrep.2016.09.034.

Abstract

We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggest that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD.

Keywords: APP; Alzheimer’s disease; FAD; PS1; endocytosis; iPSC; transcytosis.

Publication types

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

MeSH terms

  • Alzheimer Disease / pathology*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / metabolism*
  • Axons / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Lipoproteins, LDL / metabolism*
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Mutation / genetics*
  • Neurons / metabolism*
  • Presenilin-1 / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcytosis*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • LRP1 protein, human
  • Lipoproteins, LDL
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Presenilin-1
  • RNA, Messenger
  • Amyloid Precursor Protein Secretases
  • rab11 protein
  • rab GTP-Binding Proteins