Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein
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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.
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iPSC-derived neurons or NGN2-induced neurons have been unable to produce the 4R Tau isoform found in adult human brains; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation.
“One of the significant hurdles in modeling AD with iPSC-derived neurons or NGN2-induced neurons for the past decade has been their inability to produce the 4R Tau isoform found in adult human brains [19–22]; only the fetal 0N3R splicing isoform is produced, even after one year of differentiation [19].”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [20]
In Results (‘Altered Expression of TAU in FTDP-17 iPSC-Derived Neurons’; page unavailable), the paper reports 4R TAU transcripts in iPSC-derived neurons, including controls, and higher levels in neurons carrying the N279K mutation. It reports predominant fetal TAU protein, not exclusive production of the fetal 0N3R isoform. The paper does not establish the claim about one year of differentiation or NGN2-induced neurons. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe increased tau burden with age in tau-V337M organoids mirrors prior observations in 2D iPSC-derived neuronal models and in the human V337M brain.
“The increased tau burden with age mirrors prior observations in 2D iPSC-derived neuronal models (Ehrlich et al., 2015; Fong et al., 2013; lovino et al., 2015; Silva et al., 2016, 2020; Wren et al., 2015) and in the human V337M brain (Spillantini et al., 1996; Spina et al., 2017).”
From ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids (2021) · cites this paper as Ehrlich et al., 2015
The Results section, “Altered Expression of TAU in FTDP-17 iPSC-Derived Neurons” (page unavailable), reports increased tau fragments and increased AT8-positive phosphorylated tau in V337M non-dopaminergic iPSC-derived neurons compared with controls. It does not report that tau burden increased as the neurons aged. Ehrlich et al. is cited for the 2D neuronal-model comparison, not for the separate claim about the human V337M brain. (LLM, conf=0.86)
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Additional file 1 of A 3D human co-culture to model neuron-astrocyte interactions in tauopathies
Batenburg, K. L., Sestito, C., Cornelissen‐Steijger, P., van Weering, J. R. T., Price, L., Heine, V. M., & Scheper, W. (2024) · Figshare · doi:10.6084/m9.figshare.26570704
Additional file 2 of A 3D human co-culture to model neuron-astrocyte interactions in tauopathies
Batenburg, K. L., Sestito, C., Cornelissen‐Steijger, P., van Weering, J. R. T., Price, L., Heine, V. M., & Scheper, W. (2024) · Figshare · doi:10.6084/m9.figshare.26570707
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- Authors
- 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.
- Affiliations
- University Hospital Münster (DE)
- Max Planck Institute for Molecular Biomedicine (DE)
- Ikerbasque (ES)
- University of Münster (DE)
- Indiana University Indianapolis (US)
- Corresponding author
- Hargus, Gunnar
- ORCID
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 5
- Issue
- 1
- Pages
- 83-96
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC4618448
- OpenAlex
- W1795598048
- Cited by
- 94
- References
- 40
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 11 · 2019: 8 · 2018: 10 · 2017: 11 · 2016: 11 · 2015: 2
- FWCI
- 8.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Deutsche Forschungsgemeinschaft (FZT 111, GA 402/18-1, SFB-TRR128-B7, STE 1835/1-1)
- Bundesministerium für Bildung und Forschung (01GN0811, 01GN1008B)
- U.S. Public Health Service (P30 AG10133)
- International Myeloma Foundation (AL121108, I-HA-111219)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- frontotemporal dementia, tau protein, MAPT mutations, induced pluripotent stem cells, iPSC-derived neurons, neurodegeneration, tau phosphorylation, oxidative stress, mitochondrial respiration, unfolded protein response, neurite outgrowth, transcriptome, drug screening
- MeSH terms
- Cell Differentiation, Gene Expression Regulation, Humans, Mitochondria, Mutation, Neurites, tau Proteins, Oxidative Stress, Gene Expression Profiling, Unfolded Protein Response, Induced Pluripotent Stem Cells, Frontotemporal Dementia
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