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

作者：Bergstrom Petra; Agholme Lotta^*; Nazir Faisal Hayat; Satir Tugce Munise; Toombs Jamie; Wellington Henrietta; Strandberg Joakim; Bontell Thomas Olsson; Kvart**erg Hlin; Holmstrom Maria; Borestrom Cecilia; Simonsson Stina; Kunath Tilo; Lindahl Anders; Blennow Kaj; Hanse Eric; Portelius Erik; Wray Selina; Zetterberg Henrik

来源：Scientific Reports, 2016, 6(1): 29200.

DOI：10.1038/srep29200

Amyloid precursor protein (APP) and its cleavage product amyloid beta (A beta) 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. alpha-Cleaved soluble APP (sAPP alpha) was secreted early during differentiation, from neuronal progenitors, while beta-cleaved soluble APP (sAPP beta) was first secreted after deep-layer neurons had formed. Short A beta peptides, including A beta 1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as A beta 1-40/42, 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 A beta 1-40/42, is associated with mature neuronal phenotypes.

• 出版日期2016-7-7