Anesthesia-Induced Hyperphosphorylation Detaches 3-Repeat Tau from Microtubules without Affecting Their Stability In Vivo
Open accessAbstract
In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously described in vivo model, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that,in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.
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Tau phosphorylation at Ser262/356 decreases tau's affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice.
“Tau phosphorylation at these sites decreases the protein’s affinity toward microtubules in vitro, in cultured cells, transgenic Drosophila, and transgenic mice [18, 19, 25–27, 50–52].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [27]
The Discussion (page unavailable) states that phosphorylation at S262 or S262/S356 prevents tau from binding microtubules. The Introduction and Results report reduced tau binding and detachment of 3-repeat tau in old transgenic hTau mice, but do not establish that Ser262/356 phosphorylation specifically caused that detachment. The paper does not substantiate the claim’s transgenic Drosophila setting or establish the site-specific effect across every listed setting. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTau proteins detached from microtubules are prone to be phosphorylated at disease-associated sites.
“tau proteins detached from microtubules are prone to be phosphorylated at disease-associated sites [19, 25–28].”
Phosphorylation of tau negatively influences its ability to bind microtubules.
“Phosphorylation of tau negatively influences its ability to bind microtubules [25–27, 51, 52].”
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
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Cites
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“3R tau has been demonstrated to bind to MTs more weakly than 4R tau (Butner and Kirschner, 1991), and to be less efficient at promoting microtubule assembly (Goedert and Jakes, 1990; Gustke et al., 1994; Panda et al., 2003).”
Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205
Goedert, M., Jakes, R., & Vanmechelen, E. (1995) · Neuroscience Letters · doi:10.1016/0304-3940(95)11484-e · Cited by 608 · see citing works
Monoclonal antibody PHF‐1 recognizes tau protein phosphorylated at serine residues 396 and 404
Otvos, L., Feiner, L., Lang, E., Szendrei, G. I., Goedert, M., & Lee, V. M. (1994) · Journal of Neuroscience Research · doi:10.1002/jnr.490390607 · Cited by 488 · cited 2× · see citing works
“, 1997); and PHF-1, phospho-Ser/Ser (Otvos et al., 1994).”
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Merrick, S. E., Trojanowski, J. Q., & Lee, V. M.-Y. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-15-05726.1997 · Cited by 143 · see citing works
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Self-citation
- Authors
- Planel, E., Krishnamurthy, P., Miyasaka, T., Liu, L., Herman, M., Kumar, A., Bretteville, A., Figueroa, H. Y., Haung Yu, W., Whittington, R. A., Davies, P., Takashima, A., Nixon, R. A., & Duff, K. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- Doshisha University (JP)
- Nathan Kline Institute for Psychiatric Research (US)
- Albert Einstein College of Medicine (US)
- RIKEN Center for Brain Science (JP)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-11-26
- Volume
- 28
- Issue
- 48
- Pages
- 12798-12807
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2610528
- OpenAlex
- W2000251927
- Cited by
- 79
- References
- 5
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 12 · 2015: 4 · 2014: 5 · 2013: 9 · 2012: 7
- FWCI
- 2.98
- 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)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institute on Aging (R01AG022102, P01AG017216, AG017216)
- National Institute of Neurological Disorders and Stroke (P01NS048447, NS048447)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- tau hyperphosphorylation, microtubule binding, microtubule stability, anesthesia-induced hypothermia, Alzheimer's disease, transgenic mice, tubulin depolymerization, tau aggregation
- MeSH terms
- Alzheimer Disease, Anesthetics, Animals, Axons, Brain, Disease Models, Animal, Female, Hypothermia, Induced, Male, Mice, Inbred C57BL, Mice, Transgenic, Microtubules, Phosphorylation, Protein Binding, tau Proteins, Trinucleotide Repeats, Microscopy, Electron, Transmission, Mice
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