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

Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-? peptide (A?) in the form of senile plaques. A? 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? peptides, suggesting that it may be a carrier protein which prevents aggregation of A?. 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? 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? 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? 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? and restores cellular viability, by preventing A? aggregation. Overall, the present study shows that extracellular ERp57 can exert a protective effect from A? toxicity and highlights it as a possible therapeutic tool in the treatment of AD. (Figure presented.)