Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation

Sci Rep. 2016 Jul 7;6:29200. doi: 10.1038/srep29200.

Abstract

Amyloid precursor protein (APP) and its cleavage product amyloid β (Aβ) have been thoroughly studied in Alzheimer's disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. α-Cleaved soluble APP (sAPPα) was secreted early during differentiation, from neuronal progenitors, while β-cleaved soluble APP (sAPPβ) was first secreted after deep-layer neurons had formed. Short Aβ peptides, including Aβ1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as Aβ1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by Aβ1-40/42, is associated with mature neuronal phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Cell Differentiation*
  • Cerebral Cortex / pathology*
  • Gene Expression Regulation
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Neurons / metabolism
  • Neurons / pathology*
  • Peptide Fragments / metabolism
  • Protein Processing, Post-Translational*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Solubility

Substances

  • Amyloid beta-Protein Precursor
  • Peptide Fragments
  • RNA, Messenger
  • Amyloid Precursor Protein Secretases