Reduced gliotransmitter release from astrocytes mediates tau-induced synaptic dysfunction in cultured hippocampal neurons.
Glia
; 65(8): 1302-1316, 2017 08.
Article
in En
| MEDLINE
| ID: mdl-28519902
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 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Synapses
/
Astrocytes
/
Tau Proteins
/
Neurotransmitter Agents
/
Hippocampus
/
Neurons
Limits:
Animals
/
Humans
Language:
En
Journal:
Glia
Journal subject:
NEUROLOGIA
Year:
2017
Type:
Article
Affiliation country:
Italy