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 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.

Astroglia and Tau: New Perspectives

“…Further studies speculated that oxidative damage leads to GFAP fragmentation, indicating dysfunction of pathological tau-harboring protoplasmic astrocytes in PSP, associated with neuronal dysfunction (Santpere and Ferrer, 2009;Song et al, 2009). Studies in cultured hippocampal neurons suggest that extracellular tau oligomers accumulate in astrocytes followed by disrupted intracellular Ca 2+ signaling and Ca 2+ -dependent release of gliotransmitters altogether contributing to synaptic dysfunction (Piacentini et al, 2017). In summary, the neuroprotective function of astroglia, in particular the proper protection of neurons from glutamate neurotoxicity, may be impaired early in tauopathies and/or astroglia may gain novel neurotoxic properties (Sidoryk-Wegrzynowicz and Struzyńska, 2019).…”

Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms

“…In AD, APOE4 astrocytes have decreased rate of synapse pruning and turnover in the brain [ 18 ]. In AD expression of GABA, the inhibitory gliotransmitter, in reactive astrocytes, is increased, whereas reduced other gliotransmitter release, especially ATP [ 22 – 24 ]. b Blood–brain barrier.…”

Synaptic Pruning by Microglia in Epilepsy

“…From these findings, it is widely believed that activated neurons secrete ATP and induce microglial process elongation. Astrocytes also release ATP in a KA-induced mouse model of SE and ATP from astrocytes could modulate neuronal activity [91,92]. Because astrocytic feet locate closely to synapses, forming tripartite synapses, it is possible that astrocytic ATP attracts microglial processes toward synapses.…”