Tau misfolding efficiently propagates between individual intact hippocampal neurons
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Abstract
Neurofibrillary tangles, formed of misfolded, hyperphosphorylated tau protein, are a pathological hallmark of several neurodegenerations, including Alzheimer's disease. Tau pathology spreads between neurons and propagates misfolding in a prion-like manner throughout connected neuronal circuits. Tauopathy is accompanied by significant neuronal death, but the relationships between initial tau misfolding, propagation across connected neurons and cytotoxicity remain unclear. In particular the immediate functional consequence of tau misfolding for the individual neuron is not well understood. Here, using microfluidic devices to recreate discretely organized neuronal connections, we show that the spread and propagation of misfolded tau between individual murine neurons is rapid and efficient; it occurs within days. The neurons containing and propagating tau pathology display selective axonal transport deficits but remain viable and electrically competent. Therefore, we demonstrate that seed-competent misfolded tau species do not acutely cause cell death, but instead initiate discrete cellular dysfunctions. SIGNIFICANCE STATEMENT Public awareness of progressive neurodegenerations such as dementias associated with aging or repetitive head trauma is rising. Protein misfolding underlies many neurodegenerative diseases including tauopathies, where the misfolded tau protein propagates pathology through connected brain circuits in a prion-like manner. Clinically, these diseases progress over the course of years. Here we show that the underlying protein misfolding propagates rapidly between individual neurons. Presence of misfolded tau is not directly cytotoxic to the neuron; the cells remain viable with limited deficits. This suggests that neurons with tau pathology could be rescued with a therapeutic disease modifier and highlights an under-appreciated time window for such therapeutic intervention.
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Hallinan et al., 2019 reported lysosome transport defects with E14 tau opposite to those observed here, but their study used more mature hippocampal neurons and observed MC1-positive tau aggregates in axons.
“Hallinan et al., 2019 reported lysosome transport defects with E14 tau opposite to those observed here, but their study used more mature hippocampal neurons and observed MC1-positive tau aggregates in axons”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Hallinan et al., 2019
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Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies
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- Authors
- Hallinan, G. I., Vargas-Caballero, M., West, J., & Deinhardt, K.
- Affiliations
- University of Southampton (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2019-10-28
- Volume
- 39
- Issue
- 48
- Pages
- 9623-9632
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6880463
- OpenAlex
- W2982293381
- Cited by
- 59
- References
- 13
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 9 · 2022: 1 · 2021: 13 · 2020: 15 · 2019: 1
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Funders
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/L007576/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- tau misfolding, tauopathy, prion-like propagation, neurofibrillary tangles, Alzheimer's disease, hippocampal neurons, neuronal viability, disease-modifying therapy, neurodegeneration
- MeSH terms
- Animals, Cells, Cultured, Hippocampus, Humans, Mice, Inbred C57BL, Neurons, tau Proteins, Protein Folding, Mice, Proteostasis Deficiencies
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