Suchergebnisse

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. ; We thank Colin Smith and Matthew Frosch for access to human tissue. We thank lab members of the Verstreken laboratory for helpful discussions, and Kristel Vennekens and An Snellinx for technical support. Support was provided by an ERC Starting Grant (260678), ERC Consolidator grant (646671), the Instituut voor Wetenschap en Technologie (IWT O&O grant), the Interuniversity Attraction Pole program by BELSPO, the research fund KU Leuven, a Methusalem grant of the Flemish government and VIB, Leuvens Universiteitsfonds (LUF) Opening the Future grant, and a Belgian-American Educational Foundation fellowship to J.M. T.S.-J., A.H. and R.J.J. receive funding from Alzheimer's Research UK, an anonymous foundation, and a Welcome Trust Institutional strategic support grant.