Interaction of Endogenous Tau Protein with Synaptic Proteins Is Regulated by N-Methyl-d-aspartate Receptor-dependent Tau Phosphorylation*
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Amyloid-β and tau protein are the two most prominent factors in the pathology of Alzheimer disease. Recent studies indicate that phosphorylated tau might affect synaptic function. We now show that endogenous tau is found at postsynaptic sites where it interacts with the PSD95-NMDA receptor complex. NMDA receptor activation leads to a selective phosphorylation of specific sites in tau, regulating the interaction of tau with Fyn and the PSD95-NMDA receptor complex. Based on our results, we propose that the physiologically occurring phosphorylation of tau could serve as a regulatory mechanism to prevent NMDA receptor overexcitation.
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Tau phosphorylation results in enhanced dendritic fyn localization coupled to a disruption of the PSD-95/NMDAR interaction and abnormal postsynaptic density ultrastructure.
“This tau phosphorylation results in enhanced dendritic fyn localization coupled to a disruption of the PSD-95/NMDAR interaction (Mondragon-Rodriguez et al., 2012) and abnormal postsynaptic density ultrastructure (Purro et al., 2012).”
From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Mondragon-Rodriguez et al., 2012
In “Endogenous Phospho-tau Interaction with Synaptic Proteins” (Fig. 6c), the paper reports that NMDA receptor activation did not change the interaction between PSD95 and the NMDA receptor subunit GluN2B—contrary to the attributed disruption. It reports increased phospho-tau–Fyn interaction and proposes a possible transient increase in synaptic Fyn, but does not establish enhanced dendritic Fyn localization. The ultrastructure claim is attached to a different citation and is not judged here. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredAβ42 drives tau phosphorylation at GSK3β epitopes.
“Aβ42 drives tau phosphorylation at GSK3β epitopes (Jo et al., 2011; Shipton et al., 2011; Mondragon-Rodriguez et al., 2012) by a variety of proposed mechanisms in the Wnt signaling pathway (Purro et al., 2012; Vargas et al., 2014).”
From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Mondragon-Rodriguez et al., 2012
The Results (Figure 1) report that five days of Aβ exposure increased tau phosphorylation at PHF-1 and AT180 in hippocampal slice cultures. The Discussion identifies both as GSK3β target sites. However, our copy calls the treatment Aβ rather than specifically Aβ42, and it reports no Aβ-induced increase at another GSK3β target, AT8; it also does not establish that GSK3β mediated the increase. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn healthy neurons, Tau is observed in the dendritic shaft as well as in pre- and post-synaptic structures.
“Interestingly, several recent studies suggest that Tau may directly regulate synaptic function and plasticity: in healthy neurons, Tau is observed in the dendritic shaft as well as in pre- and post-synaptic structures [92, 94, 156].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [92]
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Cites
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291 · see citing works
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
AMPA Receptor Trafficking and Synaptic Plasticity
Malinow, R., & Malenka, R. C. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142758 · Cited by 2,588 · see citing works
Structural basis of long-term potentiation in single dendritic spines
Matsuzaki, M., Honkura, N., Ellis-Davies, G. C. R., & Kasai, H. (2004) · Nature · doi:10.1038/nature02617 · Cited by 2,500 · see citing works
Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models
Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G.-Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R. C., Nicoll, R. A., & Mucke, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3228 · Cited by 1,123 · see citing works
Shrinkage of dendritic spines associated with long-term depression of hippocampal synapses
Zhou, Q., Homma, K. J., & Poo, M.-M. (2004) · Neuron · doi:10.1016/j.neuron.2004.11.011 · Cited by 1,025 · see citing works
The Postsynaptic Architecture of Excitatory Synapses: A More Quantitative View
Sheng, M., & Hoogenraad, C. C. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.060805.160029 · Cited by 1,003 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · see citing works
Kosik, K., & Finch, E. (1987) · The Journal of Neuroscience · doi:10.1523/jneurosci.07-10-03142.1987 · Cited by 368 · see citing works
DYRK1A BAC transgenic mice show altered synaptic plasticity with learning and memory defects
Ahn, K.-J., Jeong, H. K., Choi, H.-S., Ryoo, S.-R., Kim, Y. J., Goo, J.-S., Choi, S.-Y., Han, J.-S., Ha, I., & Song, W.-J. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.12.006 · Cited by 220 · see citing works
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Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“Missorted tau proteins at postsynaptic terminals interacts with the subunits of AMPARs and NMDARs, leading to the excessive activation of glutamate receptors, Ca influx, impaired LTP and enhanced LTD.(92,100,101) It has been demonstrated that the absence of tau proteins prevent Aβ-induced LTP impairment mouse hippocam…”
BackgroundInteraction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689 · see citing works
Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · see citing works
Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
Tardivel, M., Bégard, S., Bousset, L., Dujardin, S., Coens, A., Melki, R., Buée, L., & Colin, M. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0386-4 · Cited by 305 · see citing works
Tau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage
Shafiei, S. S., Guerrero-Muñoz, M. J., & Castillo-Carranza, D. L. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00083 · Cited by 314 · see citing works
Microtubule-associated protein tau is essential for long-term depression in the hippocampus
Kimura, T., Whitcomb, D. J., Jo, J., Regan, P., Piers, T., Heo, S., Brown, C., Hashikawa, T., Murayama, M., Seok, H., et al. (2014) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2013.0144 · Cited by 307 · see citing works
Dendritic Tau in Alzheimer’s Disease
Ittner, A., & Ittner, L. M. (2018) · Neuron · doi:10.1016/j.neuron.2018.06.003 · Cited by 278 · see citing works
Dysfunction of NMDA receptors in Alzheimer’s disease
Zhang, Y., Li, P., Feng, J., & Wu, M. (2016) · Neurological Sciences · doi:10.1007/s10072-016-2546-5 · Cited by 282 · see citing works
“However, the acute NMDA receptor-dependent tau phosphorylation is reversible whereas tau phosphorylation after 5 days of A b exposure is not [57].”
BackgroundFrandemiche, M. L., De Seranno, S., Rush, T., Borel, E., Elie, A., Arnal, I., Lanté, F., & Buisson, A. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.4261-13.2014 · Cited by 272 · see citing works
Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities
Dorostkar, M. M., Zou, C., Blazquez-Llorca, L., & Herms, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1449-5 · Cited by 235 · see citing works
Dendritic Spine Pathology in Neurodegenerative Diseases
Herms, J., & Dorostkar, M. M. (2016) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-012615-044216 · Cited by 201 · see citing works
Tau 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
Tau Phosphorylation at Serine 396 Residue Is Required for Hippocampal LTD
Regan, P., Piers, T., Yi, J.-H., Kim, D.-H., Huh, S., Park, S. J., Ryu, J. H., Whitcomb, D. J., & Cho, K. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.2842-14.2015 · Cited by 202 · see citing works
A role for tau at the synapse in Alzheimer’s disease pathogenesis
Pooler, A. M., Noble, W., & Hanger, D. P. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.09.018 · Cited by 203 · see citing works
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
Tau Oligomers: The Toxic Player at Synapses in Alzheimer’s Disease
Guerrero-Muñoz, M. J., Gerson, J., & Castillo-Carranza, D. L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00464 · Cited by 168 · see citing works
Tau exacerbates excitotoxic brain damage in an animal model of stroke
Bi, M., Gladbach, A., van Eersel, J., Ittner, A., Przybyla, M., van Hummel, A., Chua, S. W., van der Hoven, J., Lee, W. S., Müller, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00618-0 · Cited by 167 · see citing works
GSK3β and tau protein in Alzheimer's disease and epilepsy
Toral-Rios, D., Pichardo-Rojas, P. S., Alonso-Vanegas, M., & Campos-Peña, V. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00019 · Cited by 158 · see citing works
The dendritic hypothesis for Alzheimer's disease pathophysiology
Cochran, J. N., Hall, A. M., & Roberson, E. D. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.12.004 · Cited by 114 · see citing works
Redox changes and cellular senescence in Alzheimer's disease
Yu, N., Pasha, M., & Chua, J. J. E. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103048 · Cited by 80 · see citing works
Neurogranin as biomarker in CSF is non-specific to Alzheimer's disease dementia
Willemse, E. A. J., Sieben, A., Somers, C., Vermeiren, Y., De Roeck, N., Timmers, M., Van Broeckhoven, C., De Vil, B., Cras, P., De Deyn, P. P., et al. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.08.002 · Cited by 34 · see citing works
Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice
Vargas-Caballero, M., Denk, F., Wobst, H. J., Arch, E., Pegasiou, C.-M., Oliver, P. L., Shipton, O. A., Paulsen, O., & Wade-Martins, R. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00201 · Cited by 18 · see citing works
- Authors
- Mondragón-Rodríguez, S., Trillaud-Doppia, E., Dudilot, A., Bourgeois, C., Lauzon, M., Leclerc, N., & Boehm, J.
- Affiliations
- Université de Montréal (CA)
- Corresponding author
- Boehm, Jannic
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 287
- Issue
- 38
- Pages
- 32040-32053
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3442535
- OpenAlex
- W2142118427
- Cited by
- 272
- References
- 10
- Citations by year
- 2026: 13 · 2025: 22 · 2024: 30 · 2023: 13 · 2022: 21 · 2021: 29 · 2020: 18 · 2019: 20 · 2018: 22 · 2017: 21 · 2016: 21 · 2015: 16 · 2014: 10 · 2013: 16
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- 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, tau phosphorylation, NMDA receptor, PSD-95, synaptic proteins, Fyn, postsynaptic density, synaptic function, Alzheimer's disease, amyloid-beta
- MeSH terms
- Disks Large Homolog 4 Protein, Alzheimer Disease, Animals, Gene Expression Regulation, Hippocampus, Humans, Membrane Proteins, Models, Biological, Neurons, Phosphorylation, Protein Binding, Synapses, Receptors, N-Methyl-D-Aspartate, tau Proteins, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-fyn, Rats, HEK293 Cells
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