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 and Patrik Verstreken ()
Additional contact information
Lujia Zhou: VIB-KU Leuven Center for Brain & Disease Research
Joseph McInnes: VIB-KU Leuven Center for Brain & Disease Research
Keimpe Wierda: VIB-KU Leuven Center for Brain & Disease Research
Matthew Holt: VIB-KU Leuven Center for Brain & Disease Research
Abigail G. Herrmann: University of Edinburgh, Centre for Cognitive and Neural Systems, Center for Dementia Prevention and Euan MacDonald Centre
Rosemary J. Jackson: University of Edinburgh, Centre for Cognitive and Neural Systems, Center for Dementia Prevention and Euan MacDonald Centre
Yu-Chun Wang: VIB-KU Leuven Center for Brain & Disease Research
Jef Swerts: VIB-KU Leuven Center for Brain & Disease Research
Jelle Beyens: VIB-KU Leuven Center for Brain & Disease Research
Katarzyna Miskiewicz: VIB-KU Leuven Center for Brain & Disease Research
Sven Vilain: VIB-KU Leuven Center for Brain & Disease Research
Ilse Dewachter: Catholic University of Louvain, Alzheimer Dementia Group, Institute of Neuroscience
Diederik Moechars: Janssen Research and Development
Bart De Strooper: VIB-KU Leuven Center for Brain & Disease Research
Tara L. Spires-Jones: University of Edinburgh, Centre for Cognitive and Neural Systems, Center for Dementia Prevention and Euan MacDonald Centre
Joris De Wit: VIB-KU Leuven Center for Brain & Disease Research
Patrik Verstreken: VIB-KU Leuven Center for Brain & Disease Research

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15295

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