CoChat
Sign Up
Cited by 130Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss

Open access
Tackenberg, C, Grinschgl, S, Trutzel, A, Santuccione, A C, Frey, M C, Konietzko, U, Grimm, J, Brandt, R +1 more·2013·Cell Death & Disease
DOI 10.1038/cddis.2013.129PMC PMC3641351
Open this paper in CoChat — free accountOpen PDF

Abstract

Aggregates of amyloid-beta (Aβ) and tau are hallmarks of Alzheimer's disease (AD) leading to neurodegeneration and synaptic loss. While increasing evidence suggests that inhibition of N-methyl-D-aspartate receptors (NMDARs) may mitigate certain aspects of AD neuropathology, the precise role of different NMDAR subtypes for Aβ- and tau-mediated toxicity remains to be elucidated. Using mouse organotypic hippocampal slice cultures from arcAβ transgenic mice combined with Sindbis virus-mediated expression of human wild-type tau protein (hTau), we show that Aβ caused dendritic spine loss independently of tau. However, the presence of hTau was required for Aβ-induced cell death accompanied by increased hTau phosphorylation. Inhibition of NR2B-containing NMDARs abolished Aβ-induced hTau phosphorylation and toxicity by preventing GSK-3β activation but did not affect dendritic spine loss. Inversely, NR2A-containing NMDAR inhibition as well as NR2A-subunit knockout diminished dendritic spine loss but not the Aβ effect on hTau. Activation of extrasynaptic NMDARs in primary neurons caused degeneration of hTau-expressing neurons, which could be prevented by NR2B-NMDAR inhibition but not by NR2A knockout. Furthermore, caspase-3 activity was increased in arcAβ transgenic cultures. Activity was reduced by NR2A knockout but not by NR2B inhibition. Accordingly, caspase-3 inhibition abolished spine loss but not hTau-dependent toxicity in arcAβ transgenic slice cultures. Our data show that Aβ induces dendritic spine loss via a pathway involving NR2A-containing NMDARs and active caspase-3 whereas activation of eSyn NR2B-containing NMDARs is required for hTau-dependent neurodegeneration, independent of caspase-3.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/cddis.2013.129

Cites

9 of 9 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

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

Flagged first, then by citations

Research works printed but not linked: 51

  1. Rapoport M Dawson HN Binder LI Vitek MP Ferreira A Tau is essential to beta -amyloid-induced neurotoxicity Proc Natl Acad Sci USA 2002 99 6364 6369 11959919 PMC122954
  2. Roberson E Scearce-Levie K Palop JJ Yan F Cheng IH Wu T Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model Science 2007 31 750 754 17478722
  3. Ittner LM Ke YD Delerue F Bi M Gladbach A van Eersel J Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models Cell 2010 142 387 397 20655099
  4. Nussbaum JM Schilling S Cynis H Silva A Swanson E Wangsanut T Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-ß Nature 2012 485 651 655 22660329 PMC3367389
  5. Decker H Jürgensen S Adrover MF Brito-Moreira J Bomfim TR Klein WL N-methyl-D-aspartate receptors are required for synaptic targeting of Alzheimer's toxic amyloid-ß peptide oligomers J Neurochem 2010 115 1520 1529 20950339
  6. De Felice FG Velasco PT Lambert MP Viola K Fernandez SJ Ferreira ST Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine J Biol Chem 2007 282 11590 11601 17308309
  7. Papouin T Ladépêche L Ruel J Sacchi S Labasque M Hanini M Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists Cell 2012 150 633 646 22863013
  8. Steigerwald F Schulz TW Schenker LT Kennedy MB Seeburg PH Köhr G C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors J Neurosci 2000 20 4573 4581 10844027 PMC6772457
  9. Martel MA Wyllie DJ Hardingham GE In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death Neuroscience 2009 158 334 343 18378405 PMC2635533
  10. Xia P Chen HS Zhang D Lipton SA Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses J Neurosci 2010 30 11246 11250 20720132 PMC2932667
  11. Harris AZ Pettit DL Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices J Physiol 2007 584 509 519 17717018 PMC2277145
  12. Thomas CG Miller AJ Westbrook GL Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons J Neurophysiol 2006 95 1727 1734 16319212
  13. Li S Jin M Koeglsperger T Shepardson NE Shankar GM Selkoe DJ Soluble Aß oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors J Neurosci 2011 31 6627 6638 21543591 PMC3100898
  14. Liu J Chang L Roselli F Almeida OF Gao X Wang X Amyloid-ß induces caspase-dependent loss of PSD-95 and synaptophysin through NMDA receptors J Alzheimers Dis 2010 22 541 556 20847396
  15. Texidó L Martín-Satué M Alberdi E Solsona C Matute C Amyloid ß peptide oligomers directly activate NMDA receptors Cell Calcium 2011 49 184 190 21349580
  16. Finder VH Vodopivec I Nitsch RM Glockshuber R The recombinant amyloid-beta peptide Abeta1-42 aggregates faster and is more neurotoxic than synthetic Abeta1-42 J Mol Biol 2010 396 9 18 20026079
  17. Shahani N Subramaniam S Wolf T Tackenberg C Brandt R Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices J Neurosci 2006 31 6103 6114 16738255 PMC6675219
  18. Auberson YP Allgeier H Bischoff S Lingenhoehl K Moretti R Schmutz M 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition Bioorg Med Chem Lett 2002 12 1099 1102 11909726
  19. Feng B Tse HW Skifter DA Morley R Jane DE Monaghan DT Structure-activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid Br J Pharmacol 2004 141 508 516 14718249 PMC1574223
  20. Berberich S Punnakkal P Jensen V Pawlak V Seeburg PH Hvalby Ø Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation J Neurosci 2005 25 6907 6910 16033900 PMC6725356
  21. Li X Lu F Tian Q Yang Y Wang Q Wang JZ Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture J Neural Transm 2006 113 93 102 15959856
  22. Peineau S Taghibiglou C Bradley C Wong TP Liu L Lu J LTP inhibits LTD in the hippocampus via regulation of GSK3beta Neuron 2007 53 703 717 17329210
  23. Ivanov A Pellegrino C Rama S Dumalska I Salyha Y Ben-Ari Y Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons J Physiol 2006 572 789 798 16513670 PMC1779993
  24. Hoey SE Williams RJ Perkinton MS Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production J Neurosci 2009 29 4442 4460 19357271 PMC6665739
  25. Dickson DW Yen SH Suzuki KI Davies P Garcia JH Hirano A Ballooned neurons in select neurodegenerative diseases contain phosphorylated neurofilament epitopes Acta Neuropathol 1986 71 216 223 2432750
  26. D'Amelio M Cavallucci V Middei S Marchetti C Pacioni S Ferri A Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease Nat Neurosci 2011 14 69 76 21151119
  27. Jin M Shepardson N Yang T Chen G Walsh D Selkoe DJ Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration Proc Natl Acad Sci USA 2011 108 5819 5824 21421841 PMC3078381
  28. Blurton-Jones M Laferla FM Pathways by which Abeta facilitates tau pathology Curr Alzheimer Res 2006 3 437 448 17168643
  29. Gong CX Singh TJ Grundke-Iqbal I Iqbal K Phosphoprotein phosphatase activities in Alzheimer disease brain J Neurochem 1993 61 921 927 8395566
  30. Desikan RS McEvoy LK Thompson WK Holland D Roddey JC Blennow K Amyloid-ß associated volume loss occurs only in the presence of phospho-tau Ann Neurol 2011 70 657 661 22002658 PMC3368003
  31. Harada A Oguchi K Okabe S Kuno J Terada S Ohshima T Altered microtubule organization in small-calibre axons of mice lacking tau protein Nature 1994 269 488 491 8202139
  32. Dawson HN Ferreira A Eyster MV Ghoshal N Binder LI Vitek MP Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice J Cell Sci 2001 114 1179 1187 11228161
  33. Tucker KL Meyer M Barde YA Neurotrophins are required for nerve growth during development Nat Neurosci 2001 4 29 37 11135642
  34. Muramatsu K Hashimoto Y Uemura T Kunii M Harada R Sato T Neuron-specific recombination by Cre recombinase inserted into the murine tau locus Biochem Biophys Res Commun 2008 370 419 423 18381201
  35. Roberson ED Halabisky B Yoo JW Yao J Chin J Yan F Amyloid-ß/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease J Neurosci 2011 31 700 711 21228179 PMC3325794
  36. Vossel KA Zhang K Brodbeck J Daub AC Sharma P Finkbeiner S Tau reduction prevents Abeta-induced defects in axonal transport Science 2010 330 198 20829454 PMC3024010
  37. Gauthier-Kemper A Weissmann C Golovyashkina N Sebö-Lemke Z Drewes G Gerke V The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner J Cell Biol 2011 192 647 661 21339331 PMC3044115
  38. Martel MA Ryan TJ Bell KF Fowler JH McMahon A Al-Mubarak B The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults Neuron 2012 74 543 556 22578505 PMC3398391
  39. Massey PV Johnson BE Moult PR Auberson YP Brown MW Molnar E Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression J Neurosci 2004 24 7821 7828 15356193 PMC6729941
  40. Liu L Wong TP Pozza MF Lingenhoehl K Wang Y Sheng M Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity Science 2004 304 1021 1024 15143284
  41. Gambrill AC Barria A NMDA receptor subunit composition controls synaptogenesis and synapse stabilization Proc Natl Acad Sci USA 2011 108 5855 5860 21427228 PMC3078406
  42. Bordji K Becerril-Ortega J Nicole O Buisson A Activation of extrasynaptic, but not synaptic, NMDA receptors modifies amyloid precursor protein expression pattern and increases amyloid-ß production J Neurosci 2010 30 15927 15942 21106831 PMC6633754
  43. Wroge CM Hogins J Eisenman L Mennerick S Synaptic NMDA receptors mediate hypoxic excitotoxic death J Neurosci 2012 6732 6742 22573696 PMC3361974
  44. Li B Chen N Luo T Otsu Y Murphy TH Raymond LA Differential regulation of synaptic and extra-synaptic NMDA receptors Nat Neurosci 2002 5 833 834 12195433
  45. Amadoro G Ciotti MT Costanzi M Cestari V Calissano P Canu N NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation Proc Natl Acad Sci USA 2006 103 2892 2897 16477009 PMC1413822
  46. Li Z Jo J Jia JM Lo SC Whitcomb DJ Jiao S Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization Cell 2010 141 859 871 20510932 PMC2909748
  47. Jo J Whitcomb DJ Olsen KM Kerrigan TL Lo SC Bru-Mercier G Aß(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3ß Nat Neurosci 2011 14 545 547 21441921
  48. Wu HY Hudry E Hashimoto T Kuchibhotla K Rozkalne A Fan Z Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation J Neurosci 2010 30 2636 2649 20164348 PMC2841957
  49. Wu HY Hudry E Hashimoto T Uemura K Fan ZY Berezovska O Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-ß revealed by a novel fluorescence resonance energy transfer assay J Neurosci 2012 32 5298 5309 22496575 PMC3354533
  50. Kiyama Y Manabe T Sakimura K Kawakami F Mori H Mishina M Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilon1 subunit J Neurosci 1998 18 6704 6712 9712642 PMC6792962
  51. Goodger Z Rajendran L Trutzel A Kohli BM Nitsch RM Konietzko U Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway J Cell Sci 2009 122 3703 3714 19773363

Cited by

Sorted by citations

Authors
Tackenberg, C., Grinschgl, S., Trutzel, A., Santuccione, A. C., Frey, M. C., Konietzko, U., Grimm, J., Brandt, R., & Nitsch, R. M.
Affiliations
  • University of Zurich (CH)
  • Osnabrück University (DE)
Corresponding author
Tackenberg, C
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2013-04-25
Volume
4
Issue
4
Pages
e608-e608
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/cddis.2013.129
PMC
PMC3641351
OpenAlex
W1997890299
Cited by
130
References
9
Citations by year
2026: 3 · 2025: 7 · 2024: 2 · 2023: 5 · 2022: 8 · 2021: 14 · 2020: 6 · 2019: 14 · 2018: 11 · 2017: 13 · 2016: 16 · 2015: 14 · 2014: 13 · 2013: 4
FWCI
9.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • National Science Foundation
  • Velux Stiftung
  • Deutsche Forschungsgemeinschaft (Ta762/1-1, BR1192/11-2)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A, 130148)
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
NMDA receptor subunit composition, amyloid-beta, tau phosphorylation, Alzheimer's disease, dendritic spine loss, synaptic loss, NR2A, NR2B, extrasynaptic NMDA receptors, GSK3β, caspase-3, neurodegeneration, organotypic hippocampal slice cultures
MeSH terms
Glycogen Synthase Kinase 3 beta, Animals, Cells, Cultured, Hippocampus, Humans, Mice, Transgenic, Neurons, Phosphorylation, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, tau Proteins, Apoptosis, Mice, Knockout, Glycogen Synthase Kinase 3, Dendritic Spines, Mice, Caspase 3, In Vitro Techniques

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