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  Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin

Zempel, H., Luedtke, J., Kumar, Y., Biernat, J., Dawson, H., Mandelkow, E., et al. (2013). Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. Embo Journal, 32(22), 2920-2937. doi:10.1038/emboj.2013.207.

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Zempel, H., Author
Luedtke, J., Author
Kumar, Y., Author
Biernat, J., Author
Dawson, H., Author
Mandelkow, E.1, Author              
Mandelkow, E. M.1, Author              
Affiliations:
1Neuronal Cytoskeleton and Alzheimer's Disease, Cooperations, Center of Advanced European Studies and Research (caesar), Max Planck Society, ou_2173677              

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Free keywords: Abeta-oligomers spastin Tau missorting MARK/par-1 Alzheimer disease DENDRITIC SPINE MORPHOLOGY ALZHEIMERS-DISEASE TRANSGENIC MICE ENDOGENOUS TAU MOUSE MODEL PROTEIN-TAU NEURONS NEURODEGENERATION PLASTICITY NEUROTOXICITY
 Abstract: Mislocalization and aggregation of A beta and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to A beta 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 poly-glutamylation, 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 photo-convertible Dendra2-Tau, but newly synthesized. Recovery from A beta insult occurs after A beta 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 A beta 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 A beta-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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Language(s): eng - English
 Dates: 2013
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000326921400005
ISI: ISI:WOS:000326921400005
DOI: 10.1038/emboj.2013.207
ISSN: 0261-4189
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Title: Embo Journal
  Alternative Title : Embo J.
Source Genre: Journal
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Pages: - Volume / Issue: 32 (22) Sequence Number: - Start / End Page: 2920 - 2937 Identifier: -