Physiological release of endogenous tau is stimulated by neuronal activity
Open accessAbstract
Propagation of tau pathology is linked with progressive neurodegeneration, but the mechanism underlying trans-synaptic spread of tau is unknown. We show that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from healthy, mature cortical neurons. Notably, phosphorylation of extracellular tau appears reduced in comparison with intracellular tau. We also find that AMPA-induced release of tau is calcium-dependent. Blocking pre-synaptic vesicle release by tetanus toxin and inhibiting neuronal activity with tetrodotoxin both significantly impair AMPA-mediated tau release. Tau secretion is therefore a regulatable process, dysregulation of which could lead to the spread of tau pathology in disease.
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Evidence documents active secretion of tau in normal and disease conditions.
“Instead, evidence now documents active secretion of tau in normal and disease conditions.19,65”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [65]
The Introduction and Results and Discussion show regulated tau release from healthy neurons, supporting active secretion under normal conditions. The Introduction describes tau transfer in disease models, but the Results and Discussion say that presynaptic release in those models *could* explain it and that increased release in affected brain areas has not been examined. The paper therefore does not establish active secretion in disease conditions as firmly as the claim suggests. (LLM, conf=0.85)
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- Authors
- Pooler, A. M., Phillips, E. C., Lau, D. H. W., Noble, W., & Hanger, D. P.
- Affiliations
- King's College London (GB)
- Corresponding author
- Hanger, Diane P
- Venue
- The EMBO Reports
- Published
- 2013-02-15
- Volume
- 14
- Issue
- 4
- Pages
- 389-394
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC3615658
- OpenAlex
- W2134157741
- Cited by
- 642
- References
- 9
- Citations by year
- 2026: 39 · 2025: 33 · 2024: 55 · 2023: 51 · 2022: 57 · 2021: 71 · 2020: 63 · 2019: 57 · 2018: 47 · 2017: 48 · 2016: 32 · 2015: 29 · 2014: 35 · 2013: 24
- FWCI
- 27.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- EMBO Reports (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Funders
- Wellcome Trust
- Henry Smith Charity
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, neuronal activity, AMPA receptors, calcium-dependent secretion, tau phosphorylation, trans-synaptic spread, neurodegeneration, tetanus toxin, tetrodotoxin, cortical neurons
- MeSH terms
- Action Potentials, Animals, Cells, Cultured, Cerebral Cortex, Neurons, Potassium, Quinoxalines, tau Proteins, Rats, Sprague-Dawley, Receptors, AMPA, Rats, Primary Cell Culture
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