title: Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer's disease donor as a model for investigating AD-associated gene regulatory networks.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. To investigate underlying disease mechanisms, induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish.
  
  
  RESULTS
  In this study, employing iPS technology, we derived and characterized iPSCs from dermal fibroblasts of an 82-year-old female patient affected by sporadic AD. The AD-iPSCs were differentiated into neuronal cells, in order to generate disease-specific protein association networks modeling the molecular pathology on the transcriptome level of AD, to analyse the reflection of the disease phenotype in gene expression in AD-iPS neuronal cells, in particular in the ubiquitin-proteasome system (UPS), and to address expression of typical AD proteins. We detected the expression of p-tau and GSK3B, a physiological kinase of tau, in neuronal cells derived from AD-iPSCs. Treatment of neuronal cells differentiated from AD-iPSCs with an inhibitor of γ-secretase resulted in the down-regulation of p-tau. Transcriptome analysis of AD-iPS derived neuronal cells revealed significant changes in the expression of genes associated with AD and with the constitutive as well as the inducible subunits of the proteasome complex. The neuronal cells expressed numerous genes associated with sub-regions within the brain thus suggesting the usefulness of our in-vitro model. Moreover, an AD-related protein interaction network composed of APP and GSK3B among others could be generated using neuronal cells differentiated from two AD-iPS cell lines.
  
  
  CONCLUSIONS
  Our study demonstrates how an iPSC-based model system could represent (i) a tool to study the underlying molecular basis of sporadic AD, (ii) a platform for drug screening and toxicology studies which might unveil novel therapeutic avenues for this debilitating neuronal disorder.
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, 06847, Dessau, Germany. amir.hossini@klinikum-dessau.de.
authors.forename: Amir M
authors.initials: AM
authors.lastname: Hossini
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. megges@molgen.mpg.de.|Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany. megges@molgen.mpg.de.|Department of Biology, Chemistry and Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195, Berlin, Germany. megges@molgen.mpg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Megges
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. Alessandro.Prigione@mdc-berlin.de.|Current address: Max Delbrueck Center for Molecular Medicine (MDC), Robert Roessle Str. 10, D-13125, Berlin, Germany. Alessandro.Prigione@mdc-berlin.de.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. lichtner@molgen.mpg.de.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Lichtner
authors.affiliation: Cologne Center for Genomics (CCG), Institute for Genetics, University of Cologne, 50931, Cologne, Germany. mohammad.toliat@uni-koeln.de.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.affiliation: Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany. Wasco.Wruck@med.uni-duesseldorf.de.
authors.forename: Wasco
authors.initials: W
authors.lastname: Wruck
authors.affiliation: Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany. Friederike.Schroeter@med.uni-duesseldorf.de.
authors.forename: Friederike
authors.initials: F
authors.lastname: Schröter
authors.affiliation: Cologne Center for Genomics (CCG), Institute for Genetics, University of Cologne, 50931, Cologne, Germany. peter.nuernberg@uni-koeln.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Nuernberg
authors.affiliation: Institute for Transfusion Medicine Dessau, Red Cross Blood Transfusion Service NSTOB, 06847, Dessau, Germany. hartmut.kroll@bsd-nstob.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kroll
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, 06847, Dessau, Germany. emakrantonaki@yahoo.com.|Geriatrics Research Group, Department of Geriatric Medicine, Charité Universitätsmedizin Berlin, Reinickendorfer Str. 61, 13447, Berlin, Germany. emakrantonaki@yahoo.com.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Makrantonaki
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
authors.affiliation: Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, 06847, Dessau, Germany. christos.zouboulis@klinikum-dessau.de.
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zoubouliss
authors.affiliation: Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. james.adjaye@med.uni-duesseldorf.de.|Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195, Berlin, Germany. james.adjaye@med.uni-duesseldorf.de.
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001570:Benzodiazepinones / Q000494:pharmacology; D002460:Cell Line; D016000:Cluster Analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D053263:Gene Regulatory Networks / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D014019:Tissue Donors; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C529132:2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide; D001570:Benzodiazepinones; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D025801:Ubiquitin; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex