Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function.
Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function.
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DOI：
10.1111/nan.12811
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发表时间：
2022-08
影响因子：
5
通讯作者：
Grassi, Claudio
中科院分区：
文献类型：
--
作者：
Li Puma, Domenica Donatella;Ripoli, Cristian;Puliatti, Giulia;Pastore, Francesco;Lazzarino, Giacomo;Tavazzi, Barbara;Arancio, Ottavio;Piacentini, Roberto;Grassi, Claudio
Several studies reported that astrocytes support neuronal communication by the release of gliotransmitters, including ATP and glutamate. Astrocytes also play a fundamental role in buffering extracellular glutamate in the synaptic cleft, thus limiting the risk of excitotoxicity in neurons. We previously demonstrated that extracellular tau oligomers (ex-oTau), by specifically targeting astrocytes, affect glutamate-dependent synaptic transmission via a reduction in gliotransmitter release. The aim of this work was to determine if ex-oTau also impair the ability of astrocytes to uptake extracellular glutamate, thus further contributing to ex-oTau-dependent neuronal dysfunction. Primary cultures of astrocytes and organotypic brain slices were exposed to ex-oTau (200 nM) for 1 hour. Extracellular glutamate buffering by astrocytes was studied by: Na+ imaging; electrophysiological recordings; high-performance liquid chromatography; Western blot and immunofluorescence. Experimental paradigms avoiding ex-oTau internalization (i.e., heparin pre-treatment and amyloid precursor protein knockout astrocytes) were used to dissect intracellular vs. extracellular effects of oTau. Ex-oTau uploading in astrocytes significantly affected glutamate-transporter-1 expression and function, thus impinging on glutamate buffering activity. Ex-oTau also reduced Na-K-ATPase activity because of pump mislocalization on the plasma membrane, with no significant changes in expression. This effect was independent of oTau internalization and it caused Na+ overload and membrane depolarization in ex-oTau-targeted astrocytes. Ex-oTau exerted a complex action on astrocytes, at both intracellular and extracellular levels. The net effect was dysregulated glutamate signalling in terms of both release and uptake that relied on reduced expression of glutamate-transporter-1, altered function and localization of NKA1A1, and NKA1A2. Consequently, Na+ gradients and all Na+-dependent transports were affected. • Extracellularly, tau oligomers cause NKAs mislocalization on the plasma membrane inducing intracellular Na+ overload in astrocytes leading to reduced Na+ gradient across the membrane; • Intracellularly, tau oligomers downregulate GLT-1 expression; • The net effects of extracellular tau oligomers is a reduction of Na+-driven uploading of extracellular glutamate from astrocytes.
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影响因子：
6.2
作者：
Li Puma, Domenica Donatella;Marcocci, Maria Elena;Grassi, Claudio
通讯作者：
Grassi, Claudio
影响因子：
4.8
作者：
Mirbaha, Hilda;Holmes, Brandon B.;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
DOI：
10.1007/978-1-4939-7816-8_7
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Argyrousi EK;Staniszewski A;Nicholls RE;Arancio O
通讯作者：
Arancio O
影响因子：
3
作者：
Meier, Silke D.;Kovalchuk, Yury;Rose, Christine R.
通讯作者：
Rose, Christine R.
影响因子：
15.9
作者：
Puzzo, Daniela;Argyrousi, Elentina K.;Arancio, Ottavio
通讯作者：
Arancio, Ottavio