Universität zu Köln

Hossini, Amir M., Megges, Matthias, Prigione, Alessandro, Lichtner, Bjoern, Toliat, Mohammad R., Wruck, Wasco, Schroter, Friederike, Nuernberg, Peter, Kroll, Hartmut, Makrantonaki, Eugenia, Zoubouliss, Christos C. and Adjaye, James (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. LONDON: BMC. ISSN 1471-2164

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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 gamma-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hossini, Amir M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Megges, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Prigione, Alessandro UNSPECIFIED UNSPECIFIED UNSPECIFIED Lichtner, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wruck, Wasco UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroter, Friederike UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kroll, Hartmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Makrantonaki, Eugenia UNSPECIFIED UNSPECIFIED UNSPECIFIED Zoubouliss, Christos C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Adjaye, James UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-407634
DOI:	10.1186/s12864-015-1262-5
Journal or Publication Title:	BMC Genomics
Volume:	16
Date:	2015
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1471-2164
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language UBIQUITIN PROTEASOME SYSTEM; AMYLOID-BETA-PEPTIDE; PROTEIN-TAU; POLYMORPHISM; HYPOTHESIS; MUTATIONS; INDUCTION; PATHWAY; TARGET; NEDD8 Multiple languages Biotechnology & Applied Microbiology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40763