TY  - JOUR
AU  - Zempel, Hans
AU  - Luedtke, Julia
AU  - Kumar, Yatender
AU  - Biernat, Jacek
AU  - Dawson, Hana
AU  - Mandelkow, Eckhard
AU  - Mandelkow, Eva-Maria
TI  - Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.
JO  - The EMBO journal
VL  - 32
IS  - 22
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2020-03443
SP  - 2920-2937
PY  - 2013
AB  - 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.
KW  - Adenosine Triphosphatases: physiology
KW  - Amyloid beta-Peptides: chemistry
KW  - Amyloid beta-Peptides: physiology
KW  - Animals
KW  - Cells, Cultured
KW  - Glutamic Acid: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - Microtubules: physiology
KW  - Peptide Synthases: physiology
KW  - Rats
KW  - Spastin
KW  - Synapses: pathology
KW  - tau Proteins: genetics
KW  - tau Proteins: physiology
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Mapt protein, mouse (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Glutamic Acid (NLM Chemicals)
KW  - Adenosine Triphosphatases (NLM Chemicals)
KW  - Spastin (NLM Chemicals)
KW  - Spast protein, mouse (NLM Chemicals)
KW  - Peptide Synthases (NLM Chemicals)
KW  - TTLL6 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24065130
C2  - pmc:PMC3831312
DO  - DOI:10.1038/emboj.2013.207
UR  - https://pub.dzne.de/record/137121
ER  -