title: Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation.
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.
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Bergström
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Agholme
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Faisal Hayat
authors.initials: FH
authors.lastname: Nazir
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Tugce Munise
authors.initials: TM
authors.lastname: Satir
authors.affiliation: UCL Institute of Neurology, Department of Molecular Neuroscience, University College London, Queen Square, London, WC1N 3BG, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Toombs
authors.affiliation: UCL Institute of Neurology, Department of Molecular Neuroscience, University College London, Queen Square, London, WC1N 3BG, UK.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Wellington
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Joakim
authors.initials: J
authors.lastname: Strandberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.|Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, S-413 45, Gothenburg, Sweden.
authors.forename: Thomas Olsson
authors.initials: TO
authors.lastname: Bontell
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
authors.forename: Hlin
authors.initials: H
authors.lastname: Kvartsberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Holmström
authors.affiliation: Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Boreström
authors.affiliation: Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Simonsson
authors.affiliation: MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, Edinburgh, EH16 4UU, UK.
authors.forename: Tilo
authors.initials: T
authors.lastname: Kunath
authors.affiliation: Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Lindahl
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Institute of Neuroscience and Physiology, Department of Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-405 30, Gothenburg, Sweden.
authors.forename: Eric
authors.initials: E
authors.lastname: Hanse
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: UCL Institute of Neurology, Department of Molecular Neuroscience, University College London, Queen Square, London, WC1N 3BG, UK.
authors.forename: Selina
authors.initials: S
authors.lastname: Wray
authors.affiliation: UCL Institute of Neurology, Department of Molecular Neuroscience, University College London, Queen Square, London, WC1N 3BG, UK.|Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
mesh_terms: D000200:Action Potentials; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012995:Solubility
chemical_list: D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases