Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation.
Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation.
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DOI：
10.1038/srep29200
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发表时间：
2016-07-07
影响因子：
4.6
通讯作者：
Zetterberg H
中科院分区：
文献类型：
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作者：
Bergström P;Agholme L;Nazir FH;Satir TM;Toombs J;Wellington H;Strandberg J;Bontell TO;Kvartsberg H;Holmström M;Boreström C;Simonsson S;Kunath T;Lindahl A;Blennow K;Hanse E;Portelius E;Wray S;Zetterberg H
淀粉样前体蛋白(APP)及其裂解产物淀粉样蛋白(Aβ，Aβ)在阿尔茨海默病中已被深入研究。然而，APP似乎对神经元发育也很重要。诱导多能干细胞(IPSCs)向皮质神经元分化使体外对人类神经元发育的机制研究成为可能。在这里，我们研究了100天内人IPSCs向皮质神经元分化过程中APP的表达和蛋白降解过程。在神经元分化过程中，APP的表达保持稳定，而APP的处理过程发生了变化。α裂解的可溶性APP(sAPPα)是在分化早期从神经元前体细胞分泌的，而β裂解的可溶性APP(sAPPβ)是在深层神经元形成后首先分泌的。短的Aβ多肽，包括Aβ1-15/16，在祖细胞阶段达到顶峰，而加工转移到较长的多肽，如Aβ1-40/42，出现有丝分裂后神经元。这表明APP的处理在皮质神经元的分化过程中受到调控，Aβ1-40/42所反映的淀粉样变性APP的处理与成熟的神经元表型有关。
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.