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

Petra Bergström, Lotta Agholme, Faisal Hayat Nazir, Tugce Munise Satir, Jamie Toombs, Henrietta Wellington, Joakim Strandberg, Thomas Olsson Bontell, Hlin Kvartsberg, Maria Holmström, Cecilia Boreström, Stina Simonsson, Tilo Kunath, Anders Lindahl*, Kaj Blennow, Eric Hanse, Erik Portelius, Selina Wray, Henrik Zetterberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number29200
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 7 Jul 2016

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