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Reversible Paired Helical Filament-Like Phosphorylation of Tau Is an Adaptive Process Associated with Neuronal Plasticity in Hibernating Animals
Open accessAbstract
Neurofibrillary pathology [paired helical filaments (PHFs)] formed by the microtubule-associated protein tau in a hyperphosphorylated form is a major hallmark of Alzheimer's disease and related disorders. The process of tau phosphorylation, thought to be of critical importance for PHF formation, and its potential link to neurodegeneration, however, is not understood very well, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. Here we describe the formation of highly phosphorylated tau, containing a number of PHF-like epitopes in torpor during hibernation. PHF-like phosphorylation of tau was not associated with fibril formation and was fully reversible after arousal. Distribution of PHF-like tau followed a consistent pattern, being most intense in the entorhinal cortex, hippocampus, and isocortical areas. Within the hippocampus, a particularly high labeling was seen in CA3 pyramidal cells. Somewhat lesser reactivity was present in CA1 neurons while dentate gyrus granule cells were not reactive. Formation of PHF-like tau in CA3 neurons was paralleled by the regression of synaptic contacts of the mossy fiber system terminating on CA3 apical dendrites. Mossy fiber afferentation was re-established during arousal, concomitantly with the decrease of PHF-like tau in CA3 neurons. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau. The repeated formation and degradation of PHF-like tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. Hibernation will, therefore, be a valuable model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological in vivo conditions.
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“This implies that reorganization of the cytoskeleton is taking place rapidly and reversibly, and that changes in dendrite length and branching are not “damage,” but a form of structural plasticity.”
From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [71]
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“Studies on the European ground squirrel demonstrated that PHF-like phosphorylation is induced in the brain during the hibernation of these animals (Arendt et al., 2003), which is similar to the characteristic increase in tau phosphorylation (Avila et al., 2004).”
From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Arendt et al., 2003
In the citing paper
“and alters microtubule associated proteins, including the phosphorylation of a soluble form of tau, which is increased in hibernation and reversed when hibernation is terminated (Arendt et al., 2003).”
From Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators (2008) · cites this paper as Arendt et al., 2003
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“Indeed, in species of mammals that hibernate, dendritic remodeling is a reversible process, and occurs within hours of the onset of hibernation in European hamsters and ground squirrels, and it is also reversible within hours of wakening of the animals from torpor.60,61,71”
From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [71]
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Cited by
Sorted by citations
Physiology and neurobiology of stress and adaptation: central role of the brain
McEwen, B. S. (2007) · Physiological Reviews · doi:10.1152/physrev.00041.2006 · Cited by 5,429
Tau in physiology and pathology
Wang, Y., & Mandelkow, E. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.1 · Cited by 2,251
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McEwen, B. S., & Gianaros, P. J. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05331.x · Cited by 1,715
Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex
McEwen, B. S., Nasca, C., & Gray, J. D. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.171 · Cited by 1,574
Metadata
- Authors
- Arendt, T., Stieler, J., Strijkstra, A. M., Hut, R. A., Rüdiger, J., Van der Zee, E. A., Harkany, T., Holzer, M., & Härtig, W.
- Affiliations
- University of Groningen (NL)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-08-06
- Volume
- 23
- Issue
- 18
- Pages
- 6972-6981
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740664
- OpenAlex
- W2116508134
- Cited by
- 357
- References
- 82
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 11 · 2023: 10 · 2022: 13 · 2021: 25 · 2020: 10 · 2019: 24 · 2018: 20 · 2017: 30 · 2016: 19 · 2015: 19 · 2014: 19 · 2013: 15 · 2012: 18
- FWCI
- 6.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- European Commission (QLK-6-CT-1999-02112)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- tau phosphorylation, paired helical filaments, hibernation, torpor, neuroplasticity, mossy fiber synapses, CA3 neurons, entorhinal cortex, arousal, neurofibrillary pathology, reversible phosphorylation
- MeSH terms
- Adaptation, Physiological, Animals, Arousal, Body Temperature, Hibernation, Hippocampus, Neuronal Plasticity, Neurons, Periodicity, Phosphorylation, Sciuridae, Seasons, Synapses, tau Proteins, Mossy Fibers, Hippocampal
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