Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau

Neuron. 2018 Feb 21;97(4):823-835.e8. doi: 10.1016/j.neuron.2018.01.022. Epub 2018 Feb 1.


Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimer's disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre- and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimer's disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau.

Keywords: Alzheimer’s disease; Synaptogyrin-3; Syngr3; Tau; Tauopathy; neurodegeneration; presynapse; synapse; synaptic dysfunction; synaptic vesicles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Animals
  • Disease Models, Animal
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster
  • Female
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / metabolism
  • Presynaptic Terminals / metabolism*
  • Primary Cell Culture
  • Synaptic Vesicles / metabolism*
  • Synaptogyrins / metabolism*
  • Tauopathies / metabolism
  • tau Proteins / metabolism*


  • Drosophila Proteins
  • MAPT protein, human
  • Mapt protein, mouse
  • Synaptogyrins
  • Syngr3 protein, mouse
  • tau Proteins