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Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells
Open accessAbstract
Neuronal inclusions of hyperphosphorylated and aggregated tau protein are a pathological hallmark of several neurodegenerative tauopathies, including Alzheimer's disease (AD). The hypothesis of tau transmission in AD has emerged from histopathological studies of the spatial and temporal progression of tau pathology in postmortem patient brains. Increasing evidence in cellular and animal models supports the phenomenon of intercellular spreading of tau. However, the molecular and cellular mechanisms of pathogenic tau transmission remain unknown. The studies described herein investigate tau pathology propagation using human neurons derived from induced pluripotent stem cells. Neurons were seeded with full-length human tau monomers and oligomers and chronic effects on neuronal viability and function were examined over time. Tau oligomer-treated neurons exhibited an increase in aggregated and phosphorylated pathological tau. These effects were associated with neurite retraction, loss of synapses, aberrant calcium homeostasis, and imbalanced neurotransmitter release. In contrast, tau monomer treatment did not produce any measureable changes. This work supports the hypothesis that tau oligomers are toxic species that can drive the spread of tau pathology and neurodegeneration. SIGNIFICANCE STATEMENT Several independent studies have implicated tau protein as central to Alzheimer's disease progression and cell-to-cell pathology propagation. In this study, we investigated the ability of different tau species to propagate pathology in human neurons derived from induced pluripotent stem cells, which to date has not been shown. We demonstrated that tau oligomers, but not monomers, induce accumulation of pathological, hyperphosphorylated tau. This effect was accompanied with neurite degeneration, loss of synapses, aberrant calcium homeostasis, imbalanced neurotransmitter release, and ultimately with neuronal death. This study bridges various tau pathological phenotypes into a single and relevant induced pluripotent stem cell neuronal model of human disease that can be applied to the discovery of the mechanisms of tau-induced neurodegeneration.
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“Conflicting studies have shown varying results regarding tau uptake with some studies showing internalization of small monomeric or oligomeric tau species13 and others suggesting that only oligomeric and/or fibrillized tau is internalized14.”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [13]
In the citing paper
“The formation of oligomers was observed after 4 h of shaking, whereas fibril formation was formed after 5 days13.”
From Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs) (2018) · cites this paper as [13]
In the citing paper
“For example, in cell models, soluble oligomeric tau can induce seeding of native tau54,64, and small tau aggregates isolated from patients or animals with AD can induce tau pathology in mice54,64,65.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [65]
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Metadata
- Authors
- Usenovic, M., Niroomand, S., Drolet, R. E., Yao, L., Gaspar, R. C., Hatcher, N. G., Schachter, J., Renger, J. J., & Parmentier-Batteur, S.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-10-21
- Volume
- 35
- Issue
- 42
- Pages
- 14234-14250
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6605424
- OpenAlex
- W2176311229
- Cited by
- 245
- References
- 66
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 28 · 2023: 27 · 2022: 32 · 2021: 22 · 2020: 26 · 2019: 19 · 2018: 17 · 2017: 20 · 2016: 21
- FWCI
- 14.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau oligomers, tauopathy, Alzheimer's disease, hyperphosphorylated tau, neurodegeneration, iPSC-derived neurons, neuronal viability, neurite retraction, synaptic loss, calcium homeostasis, neurotransmitter release, cell-to-cell transmission
- MeSH terms
- Analysis of Variance, Calcium, Cell Survival, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Humans, Male, Nerve Degeneration, Neurons, Phosphorylation, tau Proteins, Neurotransmitter Agents, Microscopy, Atomic Force, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Protein Transport, Microfluidics, Induced Pluripotent Stem Cells
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