Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus
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Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease.
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Tau's role in regulating synapses does not appear to be redundant or functionally compensated in Tau knockout mice.
“Importantly, Tau’s role in regulating synapses does not appear to be redundant or functionally compensated in Tau knockout mice, suggesting a physiological role for Tau in synapses [151].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [151]
The passages available from our copy are bibliographic information and a list of keywords, not findings about Tau knockout mice. Searches for synaptic function and compensation in Tau knockout or tau-deficient mice returned no relevant passage, so the claim cannot be assessed from this copy. (LLM, conf=0.72)
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GSK‐3 in Neurodegenerative Diseases
Lei, P., Ayton, S., Bush, A. I., & Adlard, P. A. (2011) · International Journal of Alzheimer’s Disease · doi:10.4061/2011/189246 · Cited by 177 · see citing works
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Dourlen, P., Kilinc, D., Malmanche, N., Chapuis, J., & Lambert, J.-C. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02004-0 · Cited by 168 · see citing works
Central role of glucocorticoid receptors in Alzheimer's disease and depression
Canet, G., Chevallier, N., Zussy, C., Desrumaux, C., & Givalois, L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00739 · Cited by 106 · see citing works
- Authors
- Yi, J. H., Brown, C., Whitehead, G., Piers, T., Lee, Y. S., Perez, C. M., Regan, P., Whitcomb, D. J., & Cho, K.
- Affiliations
- University of Bristol (GB)
- Chonnam National University (KR)
- Corresponding author
- Cho, Kwangwook
- ORCID
- Venue
- Pharmacological Research
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 121
- Pages
- 42-51
- ISSN
- 1043-6618 (ISSN-L)
- OpenAlex
- W2606714667
- Cited by
- 36
- References
- 1
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 5 · 2017: 2
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Pharmacological Research (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, cc-by-nc-nd)
- UCL Discovery (University College London) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by-nc-nd)
- Funders
- Rosetrees Trust
- Medical Research Council (MC_G1000734)
- Biotechnology and Biological Sciences Research Council (BB/N001893/1, BB/G003963/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- glucocorticoids, long-term depression, glycogen synthase kinase-3, tau phosphorylation, hippocampus, stress, neurodegeneration, synaptic function, cognitive impairment
- MeSH terms
- Animals, Glucocorticoids, Hippocampus, Phosphorylation, Synapses, Signal Transduction, tau Proteins, Long-Term Potentiation, Glycogen Synthase Kinase 3, Rats
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