137121 20240619104349.0 10.1038/emboj.2013.207 doi pmid:24065130 pmid pmc:PMC3831312 pmc 0261-4189 ISSN 1460-2075 ISSN altmetric:1817508 altmetric DZNE-2020-03443 English 570 Zempel, Hans P:(DE-2719)2814068 0 First author Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin. Hoboken, NJ [u.a.] 2013 Wiley online Crossref Wiley 2013-09-24 print Crossref Wiley 2013-11-13 article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1718786573_8365 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 342 - Disease Mechanisms and Model Systems (POF3-342) G:(DE-HGF)POF3-342 POF3-342 POF III 0 2015-09-01 Crossref http://doi.wiley.com/10.1002/tdm_license_1.1 Dataset connected to CrossRef, PubMed, Amyloid beta-Peptides NLM Chemicals Mapt protein, mouse NLM Chemicals tau Proteins NLM Chemicals Glutamic Acid 3KX376GY7L NLM Chemicals Adenosine Triphosphatases EC 3.6.1.- NLM Chemicals Spastin EC 3.6.4.3 NLM Chemicals Spast protein, mouse EC 5.6.1.1 NLM Chemicals Peptide Synthases EC 6.3.2.- NLM Chemicals TTLL6 protein, mouse EC 6.3.2.- NLM Chemicals Adenosine Triphosphatases: physiology MeSH Amyloid beta-Peptides: chemistry MeSH Amyloid beta-Peptides: physiology MeSH Animals MeSH Cells, Cultured MeSH Glutamic Acid: metabolism MeSH Mice MeSH Mice, Knockout MeSH Microtubules: physiology MeSH Peptide Synthases: physiology MeSH Rats MeSH Spastin MeSH Synapses: pathology MeSH tau Proteins: genetics MeSH tau Proteins: physiology MeSH Luedtke, Julia P:(DE-2719)9001188 1 dzne Kumar, Yatender P:(DE-2719)2813469 2 Biernat, Jacek P:(DE-2719)2810342 3 Dawson, Hana P:(DE-HGF)0 4 Mandelkow, Eckhard P:(DE-2719)2541671 5 Mandelkow, Eva-Maria P:(DE-2719)2541658 6 Last author 10.1038/emboj.2013.207 : Wiley, 2013-09-24 22 2920-2937 journal-article Crossref The EMBO Journal 32 2013 0261-4189 10.1038/emboj.2013.207 Vol. 32, no. 22, p. 2920 - 2937 PERI:(DE-600)1467419-1 22 32:22<2920 - 2937 2920-2937 The EMBO journal 32 2013 0261-4189 Pubmed Central http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831312 http://pub.dzne.de/record/137121/files/DZNE-2020-03443_Restricted.pdf http://pub.dzne.de/record/137121/files/DZNE-2020-03443_Restricted.pdf?subformat=pdfa pdfa VDB oai:pub.dzne.de:137121 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2814068 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 1 P:(DE-2719)9001188 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2813469 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-2719)2810342 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 5 P:(DE-2719)2541671 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)2541658 DE-HGF Gesundheit Erkrankungen des Nervensystems G:(DE-HGF)POF3-340 G:(DE-HGF)POF3-342 G:(DE-HGF)POF3 G:(DE-HGF)POF3-300 G:(DE-HGF)POF Disease Mechanisms and Model Systems 0 2013 JCR StatID:(DE-HGF)0100 StatID EMBO J : 2017 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS DBCoverage StatID:(DE-HGF)0300 StatID Medline DBCoverage StatID:(DE-HGF)0310 StatID NCBI Molecular Biology Database DBCoverage StatID:(DE-HGF)0320 StatID PubMed Central DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search Peer Review StatID:(DE-HGF)0030 StatID ASC DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List WoS 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