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Nat Commun. 2017 May 11;8:15295. doi: 10.1038/ncomms15295.

Tau association with synaptic vesicles causes presynaptic dysfunction.

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VIB-KU Leuven Center for Brain &Disease Research, Leuven 3000, Belgium.
KU Leuven, Department of Neurosciences, Leuven Research Institute for Neuroscience and Disease (LIND), Leuven 3000, Belgium.
University of Edinburgh, Centre for Cognitive and Neural Systems, Center for Dementia Prevention and Euan MacDonald Centre, Edinburgh EH8 9JZ, UK.
Catholic University of Louvain, Alzheimer Dementia Group, Institute of Neuroscience, Brussels 1200, Belgium.
University of Hasselt, Biomedical Research Institute, Hasselt 3500, Belgium.
A Division of Janssen Pharmaceutica NV, Neuroscience Department, Janssen Research and Development, Beerse 2340, Belgium.


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.

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