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

Marc Ehrlich, Anna Lena Hallmann, Peter Reinhardt, Marcos J. Araúzo-Bravo, Sabrina Korr, Albrecht Röpke, Olympia E. Psathaki, Petra Ehling, Sven G. Meuth, Adrian L. Oblak, Jill R. Murrell, Bernardino Ghetti, Holm Zaehres, Hans R. Schöler, Jared Sterneckert, Tanja Kuhlmann, Gunnar Hargus

Research output: Contribution to journalArticle

41 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)83-96
Number of pages14
JournalStem Cell Reports
Volume5
Issue number1
DOIs
StatePublished - Jul 14 2015

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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    Ehrlich, M., Hallmann, A. L., Reinhardt, P., Araúzo-Bravo, M. J., Korr, S., Röpke, A., Psathaki, O. E., Ehling, P., Meuth, S. G., Oblak, A. L., Murrell, J. R., Ghetti, B., Zaehres, H., Schöler, H. R., Sterneckert, J., Kuhlmann, T., & Hargus, G. (2015). Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein. Stem Cell Reports, 5(1), 83-96. https://doi.org/10.1016/j.stemcr.2015.06.001