Alzheimer disease specific phosphoepitopes of Tau interfere with assembly of tubulin but not binding to microtubules
Abstract
In Alzheimer disease (AD)-affected neurons, the Tau protein is found in an aggregated and hyperphosphorylated state. A common hypothesis is that Tau hyperphosphorylation causes its dissociation from the microtubular surface, with consequently a breakdown of the microtubules (MTs) and aggregation of the unbound Tau. We evaluated the effect of Tau phosphorylation on both tubulin assembly and MT binding. We show that the cyclin-dependent kinase 2/cyclin A3 kinase complex can generate the AT8 and AT180 AD-specific phospho-epitopes and use NMR spectroscopy to validate qualitatively and quantitatively the phospho content of our samples. The simultaneous presence of both epitopes disables the tubulin assembly capacity of Tau in conditions whereby Tau is the driving force for the assembly process but does not, however, inhibit MT assembly when the latter is driven by an increased tubulin concentration. When compared to the isolated MT binding repeats (K(d)=0.3 microM), the phospho-Tau retains a substantial affinity for preformed MTs (K(d)=11 nM), suggesting that the phosphorylated proline-rich region still participates in the binding event. Our results hence indicate that the sole phosphorylation at the AT8/AT180 epitopes, although leading to a functional defect for Tau, is not sufficient for its dissociation from the MT surface and subsequent aggregation as observed in AD.
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Tau phosphorylation at threonine 231 is one of the earliest events in the cascade of phosphorylation and modulates tubulin assembly.
“Tau phosphorylation at threonine 231 is one of the earliest events in the cascade of phosphorylation,57 that modulates tubulin assembly.58”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [58]
Cites
Braak, H., Alafuzoff, I., Arzberger, T., Kretzschmar, H., & Del Tredici, K. (2006) · Acta Neuropathologica · doi:10.1007/s00401-006-0127-z · Cited by 3,172 · see citing works
Phosphorylation affects the ability of tau protein to promote microtubule assembly.
Lindwall, G., & Cole, R. D. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42989-9 · Cited by 901 · see citing works
Tau phosphorylation in neuronal cell function and dysfunction
Johnson, G. V. W., & Stoothoff, W. H. (2004) · Journal of Cell Science · doi:10.1242/jcs.01558 · Cited by 624 · see citing works
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
Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain
Hasegawa, M., Morishima-Kawashima, M., Takio, K., Suzuki, M., Titani, K., & Ihara, Y. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)41890-x · Cited by 430 · see citing works
Goedert, M., Jakes, R., Crowther, R. A., Cohen, P., Vanmechelen, E., Vandermeeren, M., & Cras, P. (1994) · Biochemical Journal · doi:10.1042/bj3010871 · Cited by 375 · see citing works
Jourdain, L., Curmi, P., Sobel, A., Pantaloni, D., & Carlier, M.-F. (1997) · Biochemistry · doi:10.1021/bi971491b · Cited by 245 · see citing works
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Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology.
Ashton, N. J., Pascoal, T. A., Karikari, T. K., Benedet, A. L., Lantero-Rodriguez, J., Brinkmalm, G., Snellman, A., Schöll, M., Troakes, C., Hye, A., et al. (2021) · Acta Neuropathologica · doi:10.1007/s00401-021-02275-6 · Cited by 719 · see citing works
Prabakaran, S., Lippens, G., Steen, H., & Gunawardena, J. (2012) · WIREs Systems Biology and Medicine · doi:10.1002/wsbm.1185 · Cited by 335 · see citing works
Self-citationTau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease
Ashton, N. J., Benedet, A. L., Pascoal, T. A., Karikari, T. K., Lantero-Rodriguez, J., Brum, W. S., Mathotaarachchi, S., Therriault, J., Savard, M., Chamoun, M., et al. (2022) · eBioMedicine · doi:10.1016/j.ebiom.2022.103836 · Cited by 184 · see citing works
Louis, J. V., Martens, E., Borghgraef, P., Lambrecht, C., Sents, W., Longin, S., Zwaenepoel, K., Pijnenborg, R., Landrieu, I., Lippens, G., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1018777108 · Cited by 112 · see citing works
Self-citationSottejeau, Y., Bretteville, A., Cantrelle, F.-X., Malmanche, N., Demiaute, F., Mendes, T., Delay, C., Alves Dos Alves, H., Flaig, A., Davies, P., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0237-8 · Cited by 98 · see citing works
“Firstly, following in vitro incubation with CDK2/ CycA3 [5], we confirmed that phosphorylation levels increased at several major Tau phosphoepitopes such as pT181 (AT270), pS199, pT205, pS202-T205 (AT8, Tau-1) and pT231 (RZ3, AT180), as shown by immunoblots (Fig.”
InfluentialSelf-citationThe metamorphic nature of the Tau protein: dynamic flexibility comes at a cost
Sabbagh, J. J., & Dickey, C. A. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00003 · Cited by 31 · see citing works
“For example, when tau is phosphorylated at the AT8 (S202/T205) and AT180 (T231) sites, it loses the ability to drive microtubule assembly, but can still associate with preformed microtubules (Amniai et al., 2009).”
Background
- Authors
- Amniai, L., Barbier, P., Sillen, A., Wieruszeski, J.-M., Peyrot, V., Lippens, G., & Landrieu, I.
- Affiliations
- Université des Sciences et Technologies de Lille 1 Villeneuve d'Ascq France
- Inserm (FR)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2008-12-12
- Volume
- 23
- Issue
- 4
- Pages
- 1146-1152
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1995531595
- Cited by
- 105
- References
- 7
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 10 · 2022: 10 · 2021: 9 · 2020: 11 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 9 · 2015: 12 · 2014: 1 · 2013: 1 · 2012: 5
- FWCI
- 3.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, tau protein, tau hyperphosphorylation, tubulin assembly, microtubule binding, CDK2, proline-rich region, tau aggregation, microtubule stability
- MeSH terms
- Alzheimer Disease, Epitopes, Dose-Response Relationship, Drug, Humans, Microtubules, Phosphorylation, Protein Binding, Recombinant Proteins, Tubulin, Reproducibility of Results, tau Proteins, Nuclear Magnetic Resonance, Biomolecular, Cyclin-Dependent Kinase 2
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