Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations
Open accessAbstract
Tauopathies, such as Alzheimer’s disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development. Iovino et al. generate induced pluripotent stem cell-derived neurons from human subjects with P301L or N279K MAPT mutations, and show that the cells express adult brain pattern of tau isoforms after several months in culture. MAPT mutant neurons mature earlier than control neurons and display mutation-specific phenotypes.
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iPSC-derived neurons at DIV 7-8 predominantly express 3R tau, with 4R tau expression increasing during maturation.
“iPSC-derived neurons at DIV 7–8 predominantly express 3R tau, with 4R tau expression increasing during maturation”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Iovino et al., 2015
The Results section (‘Expression of tau isoforms in human IPSC-derived neurons’; page unavailable) supports the developmental pattern in control and P301L cells: 3R tau mRNA is present from Day 1, while 4R tau mRNA appears at Day 30 and 4R protein is detected later. It does not establish predominant 3R protein expression specifically at DIV 7–8. It also reports that N279K cells express both 3R and 4R tau mRNA from Day 1, so the claim does not apply uniformly to the studied iPSC-derived neurons. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDIV7-8 iPSC-derived neurons predominantly express 3R tau, whereas our rescue experiments used 4R0N tau.
“DIV7–8 iPSC-derived neurons predominantly express 3R tau (Iovino et al., 2010; Iovino et al., 2015; Sposito et al., 2015), whereas our rescue experiments used 4R0N tau”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Iovino et al., 2015
The Results section, “Expression of tau isoforms in human IPSC-derived neurons” (page unavailable), reports 3R tau mRNA from Day 1 in control and P301L cells, with 4R mRNA appearing at Day 30. It does not establish the tau-protein isoform balance specifically at DIV7–8, and N279K cells expressed both 3R and 4R mRNA from Day 1. The cited paper is not offered as evidence for the citing authors’ own 4R0N rescue experiments. (LLM, conf=0.85)
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- Authors
- Iovino, M., Agathou, S., González-Rueda, A., Del Castillo Velasco-Herrera, M., Borroni, B., Alberici, A., Lynch, T., O’Dowd, S., Geti, I., Gaffney, D., Vallier, L., Paulsen, O., Káradóttir, R. T., & Spillantini, M. G.
- Affiliations
- University of Cambridge (GB)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Brescia (IT)
- University College Dublin (IE)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Spillantini, Maria Grazia
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-07-27
- Volume
- 138
- Issue
- 11
- Pages
- 3345-3359
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4620511
- OpenAlex
- W2124317694
- Cited by
- 155
- References
- 3
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 15 · 2023: 10 · 2022: 10 · 2021: 14 · 2020: 15 · 2019: 15 · 2018: 11 · 2017: 17 · 2016: 13 · 2015: 6
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- CurePSP
- Wellcome Trust (091543/Z/10/Z, 97922, 098051)
- National Institute for Health and Care Research
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/C013102/1, NC/L000741/1)
- Irish Institute of Clinical Neuroscience
- Biotechnology and Biological Sciences Research Council (1167142)
- NIHR Cambridge Biomedical Research Centre
- National Institute on Aging (P30AG010133)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- MAPT mutations, tauopathy, tau isoforms, P301L mutation, iPSC-derived neurons, neuronal maturation, mitochondrial transport, tau hyperphosphorylation, alpha-synuclein, frontotemporal dementia
- MeSH terms
- Adult, Aged, Cell Line, Cells, Cultured, Female, Humans, Immunohistochemistry, Infant, Newborn, Male, Microtubules, Middle Aged, Neurons, RNA, Messenger, Case-Control Studies, tau Proteins, Patch-Clamp Techniques, Gene Expression Regulation, Developmental, Microscopy, Confocal, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Tauopathies, alpha-Synuclein, Induced Pluripotent Stem Cells
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