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Reduced gliotransmitter release from astrocytes mediates tau‐induced synaptic dysfunction in cultured hippocampal neurons
Author(s) -
Piacentini Roberto,
Li Puma Domenica Donatella,
Mainardi Marco,
Lazzarino Giacomo,
Tavazzi Barbara,
Arancio Ottavio,
Grassi Claudio
Publication year - 2017
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23163
Subject(s) - biology , extracellular , neuroscience , hippocampal formation , microbiology and biotechnology , postsynaptic potential , synaptic vesicle , intracellular , axon , biochemistry , receptor , vesicle , membrane
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 Ca 2+ signaling and Ca 2+ ‐dependent release of gliotransmitters, especially ATP. Consequently, synaptic vesicle release, the expression of pre‐ and postsynaptic 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.