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000137121 0247_ $$2doi$$a10.1038/emboj.2013.207
000137121 0247_ $$2pmid$$apmid:24065130
000137121 0247_ $$2pmc$$apmc:PMC3831312
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000137121 0247_ $$2ISSN$$a1460-2075
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000137121 037__ $$aDZNE-2020-03443
000137121 041__ $$aEnglish
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000137121 1001_ $$0P:(DE-2719)2814068$$aZempel, Hans$$b0$$eFirst author
000137121 245__ $$aAmyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.
000137121 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2013
000137121 264_1 $$2Crossref$$3online$$bWiley$$c2013-09-24
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000137121 520__ $$aMislocalization and aggregation of Aβ and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to Aβ oligomers and analysed changes in the Tau/MT system. MT breakdown occurs in dendrites invaded by Tau (Tau missorting) and is mediated by spastin, an MT-severing enzyme. Spastin is recruited by MT polyglutamylation, induced by Tau missorting triggered translocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like-6) into dendrites. Consequences are spine loss and mitochondria and neurofilament mislocalization. Missorted Tau is not axonally derived, as shown by axonal retention of photoconvertible Dendra2-Tau, but newly synthesized. Recovery from Aβ insult occurs after Aβ oligomers lose their toxicity and requires the kinase MARK (Microtubule-Affinity-Regulating-Kinase). In neurons derived from Tau-knockout mice, MTs and synapses are resistant to Aβ toxicity because TTLL6 mislocalization and MT polyglutamylation are prevented; hence no spastin recruitment and no MT breakdown occur, enabling faster recovery. Reintroduction of Tau re-establishes Aβ-induced toxicity in TauKO neurons, which requires phosphorylation of Tau's KXGS motifs. Transgenic mice overexpressing Tau show TTLL6 translocalization into dendrites and decreased MT stability. The results provide a rationale for MT stabilization as a therapeutic approach.
000137121 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000137121 542__ $$2Crossref$$i2015-09-01$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000137121 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000137121 650_7 $$2NLM Chemicals$$aMapt protein, mouse
000137121 650_7 $$2NLM Chemicals$$atau Proteins
000137121 650_7 $$03KX376GY7L$$2NLM Chemicals$$aGlutamic Acid
000137121 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aAdenosine Triphosphatases
000137121 650_7 $$0EC 3.6.4.3$$2NLM Chemicals$$aSpastin
000137121 650_7 $$0EC 5.6.1.1$$2NLM Chemicals$$aSpast protein, mouse
000137121 650_7 $$0EC 6.3.2.-$$2NLM Chemicals$$aPeptide Synthases
000137121 650_7 $$0EC 6.3.2.-$$2NLM Chemicals$$aTTLL6 protein, mouse
000137121 650_2 $$2MeSH$$aAdenosine Triphosphatases: physiology
000137121 650_2 $$2MeSH$$aAmyloid beta-Peptides: chemistry
000137121 650_2 $$2MeSH$$aAmyloid beta-Peptides: physiology
000137121 650_2 $$2MeSH$$aAnimals
000137121 650_2 $$2MeSH$$aCells, Cultured
000137121 650_2 $$2MeSH$$aGlutamic Acid: metabolism
000137121 650_2 $$2MeSH$$aMice
000137121 650_2 $$2MeSH$$aMice, Knockout
000137121 650_2 $$2MeSH$$aMicrotubules: physiology
000137121 650_2 $$2MeSH$$aPeptide Synthases: physiology
000137121 650_2 $$2MeSH$$aRats
000137121 650_2 $$2MeSH$$aSpastin
000137121 650_2 $$2MeSH$$aSynapses: pathology
000137121 650_2 $$2MeSH$$atau Proteins: genetics
000137121 650_2 $$2MeSH$$atau Proteins: physiology
000137121 7001_ $$0P:(DE-2719)9001188$$aLuedtke, Julia$$b1$$udzne
000137121 7001_ $$0P:(DE-2719)2813469$$aKumar, Yatender$$b2
000137121 7001_ $$0P:(DE-2719)2810342$$aBiernat, Jacek$$b3
000137121 7001_ $$0P:(DE-HGF)0$$aDawson, Hana$$b4
000137121 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b5
000137121 7001_ $$0P:(DE-2719)2541658$$aMandelkow, Eva-Maria$$b6$$eLast author
000137121 77318 $$2Crossref$$3journal-article$$a10.1038/emboj.2013.207$$b : Wiley, 2013-09-24$$n22$$p2920-2937$$tThe EMBO Journal$$v32$$x0261-4189$$y2013
000137121 773__ $$0PERI:(DE-600)1467419-1$$a10.1038/emboj.2013.207$$gVol. 32, no. 22, p. 2920 - 2937$$n22$$p2920-2937$$q32:22<2920 - 2937$$tThe EMBO journal$$v32$$x0261-4189$$y2013
000137121 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831312
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