PI3K–ERK1/2 activation contributes to extracellular H2O2 generation in amyloid β toxicity

Amyloid β peptide (Aβ) induces hydrogen peroxide (H2O2) and superoxide generation, leading to neuronal death. Many studies have shown the involvement of NADPH oxidase, but the isotype-specific role was not assessed. Moreover, the activation status of phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) 1/2 is unclear in extracellular H2O2 generation. In this paper, we showed that Aβ1–42 induced extracellular H2O2 generation and the resulting cytotoxicity in a concentration-dependent manner. Nox2- and Nox4-specific siRNAs suppressed H2O2 and superoxide generation. LY294002 and U0126, inhibitors of PI3K and ERK1/2, respectively, reduced H2O2 generation in concentration-dependent manners. Furthermore, PI3K activation is responsible for ERK1/2 phosphorylation. An additional increase in H2O2 generation and corresponding cytotoxicity was observed after treatment with Aβ1–42 and glutamate. These results suggest that Aβ1–42 enhances the neuronal vulnerability to oxidative injury in Alzheimer's disease (AD) by increasing H2O2 generation.

► Extracellular H2O2 generation by Aβ1–42 was quantitatively measured. ► Nox2 and Nox4 contributed to the extracellular generation of H2O2 and superoxide. ► Activation of PI3K was required for phosphorylation of ERK1/2 to induce H2O2 generation. ► Increased H2O2 generation by Aβ1–42 and glutamate enhanced neuronal cytotoxicity.