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

被引：50

作者：

Bergstrom, Petra ^{[1
]}

Agholme, Lotta ^{[1
]}

Nazir, Faisal Hayat ^{[1
]}

Satir, Tugce Munise ^{[1
]}

Toombs, Jamie ^{[2
]}

Wellington, Henrietta ^{[2
]}

Strandberg, Joakim ^{[3
]}

Bontell, Thomas Olsson ^{[3
,4
]}

Kvartsberg, Hlin ^{[5
]}

Holmstrom, Maria ^{[1
]}

Borestrom, Cecilia ^{[6
,8
]}

Simonsson, Stina ^{[6
]}

Kunath, Tilo ^{[7
]}

Lindahl, Anders ^{[6
]}

Blennow, Kaj ^{[5
]}

Hanse, Eric ^{[3
]}

Portelius, Erik ^{[5
]}

Wray, Selina ^{[2
]}

Zetterberg, Henrik ^{[2
,5
]}

机构：

[1] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-40530 Gothenburg, Sweden

[2] UCL, UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London WC1N 3BG, England

[3] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, S-40530 Gothenburg, Sweden

[4] Sahlgrens Univ Hosp, Dept Clin Pathol & Cytol, S-41345 Gothenburg, Sweden

[5] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden

[6] Univ Gothenburg, Sahlgrenska Acad, Inst Biomed, Dept Clin Chem & Transfus Med, S-40530 Gothenburg, Sweden

[7] Univ Edinburgh, Sch Biol Sci, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland

[8] AstraZeneca R&D, Discovery Sci, Pepparredsleden 1, S-43183 Molndal, Sweden

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

PLURIPOTENT STEM-CELLS; CEREBRAL-CORTEX DEVELOPMENT; ALZHEIMERS-DISEASE; BETA; SECRETASE; PEPTIDES; CLEAVAGE; MUTATION; DOMAIN; ROLES;

D O I：

10.1038/srep29200

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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