Reduced Gliotransmitter Release from Astrocytes Mediates Tau-Induced Synaptic Dysfunction in Cultured Hippocampal Neurons

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.

Main Points

• Tau oligomers enter astrocytes more efficiently than neurons.
• Tau treatment affects Ca²⁺-dependent gliotransmitter release.
• Tau induces ATP-dependent inhibition of synaptic protein expression and synaptic transmission.

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