D'Ezio Veronica, Colasanti Marco, Persichini Tiziana
Department of Sciences, University "ROMA TRE", 00146 Rome, Italy.
Antioxidants (Basel). 2021 Oct 26;10(11):1685. doi: 10.3390/antiox10111685.
Amyloid-β (Aβ) deposition, a hallmark of Alzheimer's disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of several phase II detoxifying and antioxidant genes, such as the System X subunit xCT. Here, we studied (i) the effect of the Aβ fragment 25-35 (Aβ) on Nrf2-dependent System X expression in U373 human astroglial cells and (ii) the effect of Aβ-induced astrocytic response on neuronal cell viability using an in vitro co-culture system. We found that Aβ was able to activate an antioxidant response in astrocytes, by inducing both Nrf2 activation and System X up-regulation. However, this astrocytic response caused an enhanced cell mortality of co-cultured SH-SY5Y cells, taken as a neuronal model. Consistently, the specific System X inhibitor sulfasalazine prevented the increase of both neuronal mortality and extracellular glutamate levels, thus indicating that the neurotoxic effect was due to an augmented release of glutamate through the transporter. The involvement of NMDA receptor activation in this pathway was also demonstrated using the specific inhibitor MK801 that completely restored neuronal viability at the control levels. The present study sheds light on the Nrf2/system X pathway in the toxicity induced by Aβ and may help to better understand the involvement of astrocytes in neuronal death during Alzheimer's disease.
淀粉样β蛋白（Aβ）沉积是阿尔茨海默病的一个标志，已知其会诱导自由基产生和氧化应激，从而导致神经元损伤。在氧化应激期间，几种细胞类型（包括星形胶质细胞）可激活核因子红细胞2相关因子2（Nrf2），Nrf2是几种II期解毒和抗氧化基因（如系统X亚基xCT）的调节因子。在此，我们研究了（i）Aβ片段25 - 35（Aβ）对U373人星形胶质细胞中Nrf2依赖的系统X表达的影响，以及（ii）使用体外共培养系统研究Aβ诱导的星形胶质细胞反应对神经元细胞活力的影响。我们发现，Aβ能够通过诱导Nrf2激活和系统X上调来激活星形胶质细胞中的抗氧化反应。然而，这种星形胶质细胞反应导致作为神经元模型的共培养SH - SY5Y细胞的细胞死亡率增加。同样，特异性系统X抑制剂柳氮磺胺吡啶可防止神经元死亡率和细胞外谷氨酸水平的升高，从而表明神经毒性作用是由于通过转运体增加了谷氨酸的释放。使用特异性抑制剂MK801也证明了NMDA受体激活在该途径中的作用，MK801可将神经元活力完全恢复到对照水平。本研究揭示了Aβ诱导的毒性中Nrf2/系统X途径，可能有助于更好地理解阿尔茨海默病期间星形胶质细胞在神经元死亡中的作用。
