Amyloid-ß 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System Xc.

ABSTRACT

Amyloid-ß (Aß) 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 Xc- subunit xCT. Here, we studied (i) the effect of the Aß fragment 25-35 (Aß25-35) on Nrf2-dependent System Xc- expression in U373 human astroglial cells and (ii) the effect of Aß25-35-induced astrocytic response on neuronal cell viability using an in vitro co-culture system. We found that Aß25-35 was able to activate an antioxidant response in astrocytes, by inducing both Nrf2 activation and System Xc- 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 Xc- 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 Xc- pathway in the toxicity induced by Aß25-35 and may help to better understand the involvement of astrocytes in neuronal death during Alzheimer's disease.