ERp57 chaperon protein protects neuronal cells from A beta-induced toxicity

Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-beta peptide (A beta) in the form of senile plaques. A beta can cause neurodegeneration and disrupt cognitive functions by several mechanisms, including oxidative stress. ERp57 is a protein disulfide isomerase involved in the cellular stress response and known to be present in the cerebrospinal fluid of normal individuals as a complex with A beta peptides, suggesting that it may be a carrier protein which prevents aggregation of A beta. Although several studies show ERp57 involvement in neurodegenerative diseases, no clear mechanism of action has been identified thus far. In this work, we gain insights into the interaction of A beta with ERp57, with a special focus on the contribution of ERp57 to the defense system of the cell. Here, we show that recombinant ERp57 directly interacts with the A beta(25-35) fragment in vitro with high affinity via two in silico-predicted main sites of interaction. Furthermore, we used human neuroblastoma cells to show that short-term A beta(25-35) treatment induces ERp57 decrease in intracellular protein levels, different intracellular localization, and ERp57 secretion in the cultured medium. Finally, we demonstrate that recombinant ERp57 counteracts the toxic effects of A beta(25-35) and restores cellular viability, by preventing A beta(25-35) aggregation. Overall, the present study shows that extracellular ERp57 can exert a protective effect from A beta toxicity and highlights it as a possible therapeutic tool in the treatment of AD.