Tau association with synaptic vesicles causes presynaptic dysfunction

Lujia Zhou, Joseph McInnes, Keimpe Wierda, Matthew Holt, Abigail G. Herrmann, Rosemary J. Jackson, Yu-Chun Wang, Jef Swerts, Jelle Beyens, Katarzyna Miskiewicz, Sven Vilain, Ilse Dewachter, Diederik Moechars, Bart De Strooper, Tara L. Spires-Jones, Joris De Wit, Patrik Verstreken

Research output: Contribution to journalArticlepeer-review

Abstract

Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer’s disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.
Original languageEnglish
Article number15295
Number of pages13
JournalNature Communications
Volume8
Early online date11 May 2017
DOIs
Publication statusE-pub ahead of print - 11 May 2017

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