The DOI matches its Crossref record; 85 of the 85 references it cites were found in a registry or an index.
Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin
Open accessAbstract
Mislocalization and aggregation of Aβ and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to Aβ oligomers and analysed changes in the Tau/MT system. MT breakdown occurs in dendrites invaded by Tau (Tau missorting) and is mediated by spastin, an MT-severing enzyme. Spastin is recruited by MT polyglutamylation, induced by Tau missorting triggered translocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like-6) into dendrites. Consequences are spine loss and mitochondria and neurofilament mislocalization. Missorted Tau is not axonally derived, as shown by axonal retention of photoconvertible Dendra2-Tau, but newly synthesized. Recovery from Aβ insult occurs after Aβ oligomers lose their toxicity and requires the kinase MARK (Microtubule-Affinity-Regulating-Kinase). In neurons derived from Tau-knockout mice, MTs and synapses are resistant to Aβ toxicity because TTLL6 mislocalization and MT polyglutamylation are prevented; hence no spastin recruitment and no MT breakdown occur, enabling faster recovery. Reintroduction of Tau re-establishes Aβ-induced toxicity in TauKO neurons, which requires phosphorylation of Tau's KXGS motifs. Transgenic mice overexpressing Tau show TTLL6 translocalization into dendrites and decreased MT stability. The results provide a rationale for MT stabilization as a therapeutic approach.
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“Thus, cultured neurons from tau knockout (Tau−/−) mice are not susceptible to Aβ-induced synaptic damage and neurotoxicity (Rapoport et al., 2002; Nussbaum et al., 2012; Zempel et al., 2013) or to Aβ-induced defects in axonal transport (Vossel et al., 2011).”
From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Zempel et al., 2013
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“In primary neurons, we further observed that CIP2A promoted tau translocalization to dendrites and spines, which is considered to be the key event mediating the synaptic toxicity of tau (Pooler et al., 2014; Zempel et al., 2013).”
From CIP2A Causes Tau/APP Phosphorylation, Synaptopathy, and Memory Deficits in Alzheimer’s Disease (2018) · cites this paper as Zempel et al., 2013
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Citations
Cites
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“In the present study, we focussed on the link between A b O and the neuronal cytoskeleton, notably the phosphorylation/ missorting of Tau and breakdown of MTs because these features are early hallmarks of AD (Braak and Braak, 1991; Spires-Jones et al , 2009).”
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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“In familial AD, genetic evidence points to a master role of A b aggregation, leading to downstream events including Tau hyperphosphorylation and aggregation (Haass and Selkoe, 2007; Karran et al , 2011).”
Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892
Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Ittner, L. M., Ke, Y. D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., Wölfing, H., Chieng, B. C., Christie, M. J., Napier, I. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.036 · Cited by 1,821
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Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
Kang, J.-E., Lim, M. M., Bateman, R. J., Lee, J. J., Smyth, L. P., Cirrito, J. R., Fujiki, N., Nishino, S., & Holtzman, D. M. (2009) · Science · doi:10.1126/science.1180962 · Cited by 1,565
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 · cited 4×
“This is indeed the case, since blockage of both global and Tau protein synthesis strongly reduces dendritic missorting of Tau after A b O exposure.”
InfluentialCellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers
Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W., & Strittmatter, S. M. (2009) · Nature · doi:10.1038/nature07761 · Cited by 1,560
Cited by
Sorted by citations
Tau in physiology and pathology
Wang, Y., & Mandelkow, E. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2015.1 · Cited by 2,251
Bloom (2014) · doi:10.1001/jamaneurol.2013.5847 · Cited by 2,194
The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease
Spires-Jones, T. L., & Hyman, B. T. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.004 · Cited by 1,201
Fricker, M., Tolkovsky, A. M., Borutaitė, V., Coleman, M. P., & Brown, G. C. (2018) · Physiological Reviews · doi:10.1152/physrev.00011.2017 · Cited by 1,148
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
Metadata
- Authors
- Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., & Mandelkow, E.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Duke Medical Center (US)
- Center of Advanced European Studies and Research (DE)
- Corresponding author
- Mandelkow, Eva‐Maria
- Venue
- The EMBO Journal
- Published
- 2013-09-24
- Volume
- 32
- Issue
- 22
- Pages
- 2920-2937
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC3831312
- OpenAlex
- W2122620510
- Cited by
- 283
- References
- 85
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 23 · 2023: 15 · 2022: 24 · 2021: 17 · 2020: 25 · 2019: 16 · 2018: 22 · 2017: 18 · 2016: 34 · 2015: 26 · 2014: 26 · 2013: 3
- FWCI
- 20.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Wellcome Trust (089703)
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta oligomers, tau protein, Alzheimer's disease, microtubule severing, spastin, synaptic damage, dendritic microtubules, MARK kinases, tau phosphorylation, synaptic loss, microtubule stabilization
- MeSH terms
- Spastin, Adenosine Triphosphatases, Animals, Cells, Cultured, Microtubules, Peptide Synthases, Synapses, Amyloid beta-Peptides, tau Proteins, Mice, Knockout, Glutamic Acid, Mice, Rats
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