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Stem Cell Reports. 2015 Jul 14;5(1):83-96. doi: 10.1016/j.stemcr.2015.06.001. Epub 2015 Jul 2.

Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein.

Author information

1
Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
2
Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany.
3
Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014 San Sebastián, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
4
Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany; Department of Neurology, University of Münster, 48149 Münster, Germany.
5
Institute for Human Genetics, University of Münster, 48149 Münster, Germany.
6
Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
7
Department of Neurology, University of Münster, 48149 Münster, Germany.
8
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
9
Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany.
10
Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Institute of Neuropathology, University Hospital Münster, 48149 Münster, Germany. Electronic address: gunnar.hargus@ukmuenster.de.

Abstract

Frontotemporal dementia (FTD) is a frequent form of early-onset dementia and can be caused by mutations in MAPT encoding the microtubule-associated protein TAU. Because of limited availability of neural cells from patients' brains, the underlying mechanisms of neurodegeneration in FTD are poorly understood. Here, we derived induced pluripotent stem cells (iPSCs) from individuals with FTD-associated MAPT mutations and differentiated them into mature neurons. Patient iPSC-derived neurons demonstrated pronounced TAU pathology with increased fragmentation and phospho-TAU immunoreactivity, decreased neurite extension, and increased but reversible oxidative stress response to inhibition of mitochondrial respiration. Furthermore, FTD neurons showed an activation of the unfolded protein response, and a transcriptome analysis demonstrated distinct, disease-associated gene expression profiles. These findings indicate distinct neurodegenerative changes in FTD caused by mutant TAU and highlight the unique opportunity to use neurons differentiated from patient-specific iPSCs to identify potential targets for drug screening purposes and therapeutic intervention.

PMID:
26143746
PMCID:
PMC4618448
DOI:
10.1016/j.stemcr.2015.06.001
[Indexed for MEDLINE]
Free PMC Article

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