ERp57 chaperon protein protects neuronal cells from Aβ-induced toxicity

Alzheimer's disease (AD) is a neurodegenerative disorder whose main pathological hallmark is the accumulation of Amyloid-β peptide (Aβ) in the form of senile plaques. Aβ 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 Aβ peptides, suggesting that it may be a carrier protein which prevents aggregation of Aβ. 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 Aβ 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 Aβ25-35 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 Aβ25-35 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 Aβ25-35 and restores cellular viability, by preventing Aβ25-35 aggregation. Overall, the present study shows that extracellular ERp57 can exert a protective effect from Aβ toxicity and highlights it as a possible therapeutic tool in the treatment of AD

Merging the Isonitrile-Tetrazine (4+1) Cycloaddition and the Ugi Four-Component Reaction into a Single Multicomponent Process

<p>Abstract: Multicomponent reactions are of utmost importance at generating a unique, wide, and complex</p><p>chemical space. Herein we describe a novel multicomponent approach based on the combination of the</p><p>isonitrile-tetrazine (4+1) cycloaddition and the Ugi four-component reaction to generate pyrazole amide</p><p>derivatives. The scope of the reaction as well as mechanistic insights governing the 4H-pyrazol-4-imine</p><p>tautomerization are provided. This multicomponent process provides access to a new chemical space of</p><p>pyrazole amide derivatives and offers a tool for peptide modification and stapling.</p&gt