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  Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer's disease donor as a model for investigating AD-associated gene regulatory networks

Hossini, A. M., Megges, M., Prigione, A., Lichtner, B., Toliat, M. R., Wruck, W., et al. (2015). Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer's disease donor as a model for investigating AD-associated gene regulatory networks. BMC Genomics, 16, 64. doi:10.1186/s12864-015-1262-5.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-4362-4 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-4363-2
Genre: Journal Article

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​4.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://​creativecommons.​org/​publicdomain/​zero/​1.​0/​) applies to the data made available in this article, unless otherwise stated.
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© 2015 Hossini et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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 Creators:
Hossini, Amir M1, Author
Megges, Matthias2, Author              
Prigione, Alessandro2, Author              
Lichtner, Björn2, Author              
Toliat, Mohammad R3, Author
Wruck, Wasco2, Author
Schröter, Frederike2, Author
Nuernberg, Peter3, Author
Kroll, Hartmut4, Author
Makrantonak, Eugenia1, 5, Author
Zouboulis, Christos C1, Author
Adjaye, James2, Author              
Affiliations:
1Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, 06847 Dessau, Germany, ou_persistent22              
2Molecular Embryology and Aging (James Adjaye), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479654              
3Cologne Center for Genomics (CCG), Institute for Genetics, University of Cologne, 50931 Cologne, Germany., ou_persistent22              
4Institute for Transfusion Medicine Dessau, Red Cross Blood Transfusion Service NSTOB, 06847 Dessau, Germany, ou_persistent22              
5Geriatrics Research Group, Department of Geriatric Medicine, Charité Universitätsmedizin Berlin , Reinickendorfer Str. 61, 13447 Berlin, Germany., ou_persistent22              

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Free keywords: Alzheimer ’ s disease, Skin cells, γ -secretase, Induced pluripotent stem cells, TNFRSF1A , Neuronal cells, p-tau, Transcriptome, Proteasome
 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 consti tutive 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 sporad ic AD, (ii) a platform for drug screening and toxicology studies which might unveil novel therapeutic avenues for this debilitating neuronal disorder.

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Language(s): eng - English
 Dates: 2014-04-282015-01-222015-02-14
 Publication Status: Published online
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 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1186/s12864-015-1262-5
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Title: BMC Genomics
Source Genre: Journal
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Publ. Info: BioMed Central
Pages: - Volume / Issue: 16 Sequence Number: - Start / End Page: 64 Identifier: ISSN: 1471-2164
CoNE: /journals/resource/111000136905010