Reduced gliotransmitter release from astrocytes mediates tau-induced synaptic dysfunction in cultured hippocampal neurons

Roberto Piacentini, Domenica Donatella Li Puma, Barbara Tavazzi, Claudio Grassi, Marco Mainardi, Giacomo Lazzarino, Ottavio Arancio

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

Tau is a microtubule-associated protein exerting several physiological functions in neurons. In Alzheimer’s disease (AD) misfolded tau accumulates intraneuronally and leads to axonal degeneration. However, tau has also been found in the extracellular medium. Recent studies indicated that extracellular tau uploaded from neurons causes synaptic dysfunction and contributes to tau pathology propagation. Here we report novel evidence that extracellular tau oligomers are abundantly and rapidly accumulated in astrocytes where they disrupt intracellular Ca2+ signaling and Ca2+-dependent release of gliotransmitters, especially ATP. Consequently, synaptic vesicle release, the expression of pre- and post-synaptic proteins, and mEPSC frequency and amplitude were reduced in neighboring neurons. Notably, we found that tau uploading from astrocytes required the amyloid precursor protein, APP. Collectively, our findings suggests that astrocytes play a critical role in the synaptotoxic effects of tau via reduced gliotransmitter availability, and that astrocytes are major determinants of tau pathology in AD.
Original languageEnglish
Pages (from-to)1302-1316
Number of pages15
JournalGLIA
DOIs
Publication statusPublished - 2017

Keywords

  • APP
  • Synaptic proteins
  • Synaptic transmission
  • Tauopathy
  • Tripartite synapse

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