NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation
Open accessAbstract
The altered function and/or structure of tau protein is postulated to cause cell death in tauopathies and Alzheimer’s disease. However, the mechanisms by which tau induces neuronal death remain unclear. Here we show that overexpression of human tau and of some of its N-terminal fragments in primary neuronal cultures leads to an N -methyl- d -aspartate receptor (NMDAR)-mediated and caspase-independent cell death. Death signaling likely originates from stimulation of extrasynaptic NR2B-subunit-containing NMDARs because it is accompanied by dephosphorylation of cAMP-response-element-binding protein (CREB) and it is inhibited by ifenprodil. Interestingly, activation of NMDAR leads to a crucial, sustained, and delayed phosphorylation of extracellular-regulated kinases 1 and 2, whose inhibition largely prevents tau-induced neuronal death. Moreover, NMDAR involvement causes the fatal activation of calpain, which, in turn, degrades tau protein into a 17-kDa peptide and possibly other highly toxic N-terminal peptides. Some of these peptides are hypothesized, on the basis of our in vitro experiments, to initiate a negative loop, ultimately leading to cell death. Thus, inhibition of calpain largely prevents tau degradation and cell death. Our findings unravel a cellular mechanism linking tau toxicity to NMDAR activation and might be relevant to Alzheimer’s disease and tauopathies where NMDAR-mediated toxicity is postulated to play a pivotal role.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Reduced ERK activity enhances tau-induced toxicity.
“However, reduced ERK activity has also been shown to enhance tau-induced toxicity (132)”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [132]
In “Tau Induces NMDAR-Dependent Activation of ERK1/2” (page not supplied), the paper reports that inhibiting ERK signaling or genetically removing ERK1 protects neurons from tau-induced cell death. It therefore finds the opposite of the attributed claim: reduced ERK activity lessens, rather than enhances, tau toxicity. (LLM, conf=0.93)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways
Hardingham, G. E., Fukunaga, Y., & Bading, H. (2002) · Nature Neuroscience · doi:10.1038/nn835 · Cited by 1,686 · see citing works
Regulation of NMDA receptor trafficking by amyloid-β
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., Nairn, A. C., Salter, M. W., Lombroso, P. J., Gouras, G. K., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1503 · Cited by 1,561 · see citing works
Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms
Andorfer, C., Acker, C. M., Kress, Y., Hof, P. R., Duff, K., & Davies, P. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.4637-04.2005 · Cited by 511 · see citing works
Mazzucchelli, C., Vantaggiato, C., Ciamei, A., Fasano, S., Pakhotin, P., Krezel, W., Welzl, H., Wolfer, D. P., Pagès, G., Valverde, O., et al. (2002) · Neuron · doi:10.1016/s0896-6273(02)00716-x · Cited by 456 · see citing works
Self-citationTau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis
Canu, N., Dus, L., Barbato, C., Ciotti, M. T., Brancolini, C., Rinaldi, A. M., Novak, M., Cattaneo, A., Bradbury, A., & Calissano, P. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07061.1998 · Cited by 232 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M. & Binder, L. I. (1986) Proc. Natl. Acad. Sci. USA 83, 4913-4917.
- Kraemer, B. C., Zhang, B., Leverenz, J. B., Thomas, J. H., Trojanowski, J. Q. & Schellenberg, G. D. (2003) Proc. Natl. Acad. Sci. USA 100, 9980-9985.
- Saito, K., Elce, J. S., Hamos, J. E. & Nixon R. A. (1993) Proc. Natl. Acad. Sci. USA 90, 2628-2632.
Cited by
Sorted by citations
The spectrum of disease in chronic traumatic encephalopathy
McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., Lee, H.-S., Hall, G., Wojtowicz, S. M., Baugh, C. M., et al. (2013) · Brain · doi:10.1093/brain/aws307 · Cited by 2,098 · see citing works
The Neuropathology of Chronic Traumatic Encephalopathy
McKee, A. C., Stein, T. D., Kiernan, P. T., & Alvarez, V. E. (2015) · Brain Pathology · doi:10.1111/bpa.12248 · Cited by 585 · see citing works
Jacob, C. P., Koutsilieri, E., Bartl, J., Neuen-Jacob, E., Arzberger, T., Zander, N., Ravid, R., Roggendorf, W., Riederer, P., & Grünblatt, E. (2007) · Journal of Alzheimer's Disease · doi:10.3233/jad-2007-11113 · Cited by 317 · 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
“Calpain, activated by Ca 2 ? influx through NMDAR, degrades tau protein into a toxic N-terminal peptides which leading to cell death [59].”
BackgroundTau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers
Quinn, J. P., Corbett, N. J., Kellett, K. A. B., & Hooper, N. M. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-170959 · Cited by 170 · see citing works
Rammes, G., Hasenjäger, A., Sroka-Saidi, K., Deussing, J. M., & Parsons, C. G. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.01.051 · Cited by 163 · see citing works
Funk, K. E., Thomas, S. N., Schafer, K. N., Cooper, G. L., Liao, Z., Clark, D. J., Yang, A. J., & Kuret, J. (2014) · Biochemical Journal · doi:10.1042/bj20140372 · Cited by 142 · see citing works
Corsetti, V., Florenzano, F., Atlante, A., Bobba, A., Ciotti, M. T., Natale, F., Della Valle, F., Borreca, A., Manca, A., Meli, G., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv059 · Cited by 129 · see citing works
Self-citationThe 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
Ambegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · see citing works
“shown to enhance tau-induced toxicity (132); thus, the role of ERK in neurodegeneration remains incompletely understood.”
BackgroundCleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment
Garg, S., Timm, T., Mandelkow, E.-M., Mandelkow, E., & Wang, Y. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.09.008 · Cited by 103 · see citing works
- Authors
- Amadoro, G., Ciotti, M. T., Costanzi, M., Cestari, V., Calissano, P., & Canu, N.
- Affiliations
- Institute of Neurobiology and Molecular Medicine (IT)
- National Research Council (IT)
- Libera Università Maria SS. Assunta (IT)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Canu, Nadia
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-13
- Volume
- 103
- Issue
- 8
- Pages
- 2892-2897
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1413822
- OpenAlex
- W2096557110
- Cited by
- 243
- References
- 6
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 11 · 2023: 15 · 2022: 5 · 2021: 15 · 2020: 12 · 2019: 13 · 2018: 11 · 2017: 17 · 2016: 10 · 2015: 14 · 2014: 20 · 2013: 14 · 2012: 16
- FWCI
- 9.52
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tau protein, NMDA receptor, extrasynaptic NMDA receptors, NR2B subunit, calpain, ERK signaling, tau degradation, caspase-independent cell death, neuronal cell death, tauopathy, Alzheimer's disease, ifenprodil
- MeSH terms
- Alzheimer Disease, Animals, Calpain, Cells, Cultured, Enzyme Activation, Humans, Mice, Mutant Strains, Neurons, Phosphorylation, Piperidines, Transfection, Transcriptional Activation, Cysteine Proteinase Inhibitors, Receptors, N-Methyl-D-Aspartate, tau Proteins, Rats, Wistar, Mitogen-Activated Protein Kinase 1, Caspases, Protein Kinase Inhibitors, Mitogen-Activated Protein Kinase 3, CREB-Binding Protein, Mice, Rats, Caspase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
