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ERp57 chaperon protein protects neuronal cells from Aβ-induced toxicity.

ABSTRACT: 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 Aβ_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 Aβ_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 Aβ_25-35 and restores cellular viability, by preventing Aβ_25-35 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.

SUBMITTER: Di Risola D

PROVIDER: S-EPMC9543391 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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ERp57 chaperon protein protects neuronal cells from Aβ-induced toxicity.

Di Risola Daniel D Ricci Daniela D Marrocco Ilaria I Giamogante Flavia F Grieco Maddalena M Francioso Antonio A Vasco-Vidal Aldrin A Mancini Patrizia P Colotti Gianni G Mosca Luciana L Altieri Fabio F

Journal of neurochemistry 20220708 4

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 ...[more]

PMID: 35699375

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Project description:BackgroundExtracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aβ neurotoxicity in AD remains unknown.MethodsIn the present study, the characteristic expressions of MANF in Aβ1-42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aβ1-42 exposure were also investigated.ResultsThe results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aβ1-42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aβ1-42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aβ1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aβ1-42 exposure, whereas knockdown of MANF has the opposite effect.ConclusionsThese findings demonstrate that MANF may exert neuroprotective effects against Aβ-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.

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ERp57 chaperon protein protects neuronal cells from Aβ-induced toxicity.

Publications

ERp57 chaperon protein protects neuronal cells from Aβ-induced toxicity.

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