Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.
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.
DZNE, German Center for Neurodegenerative Diseases, Bonn, Germany.
Hans
H
Zempel
Julia
J
Luedtke
Yatender
Y
Kumar
Jacek
J
Biernat
Hana
H
Dawson
Eckhard
E
Mandelkow
Eva-Maria
EM
Mandelkow
D000251:Adenosine Triphosphatases / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000502:physiology*; D010453:Peptide Synthases / Q000502:physiology*; D051381:Rats; D000074181:Spastin; D013569:Synapses / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000502:physiology*
D016229:Amyloid beta-Peptides; C558298:Mapt protein, mouse; D016875:tau Proteins; D018698:Glutamic Acid; D000251:Adenosine Triphosphatases; D000074181:Spastin; C498515:Spast protein, mouse; D010453:Peptide Synthases; C585750:TTLL6 protein, mouse