Role of Ero1α in cognitive impairment induced by chronic hypoxia.

Recent reports suggested the endoplasmic reticulum stress (ERS)-associated pathway is involved with cognitive impairment in hypoxia condition. ERO1-like protein alpha (Ero1α), an endoplasmic reticulum membrane-bound N-glycoprotein, has been reported to promote oxidative protein folding. However, no studies have reported whether the Ero1α is trapped in hypoxia-induced neuronal loss through the ERS-associated pathways. In our study, this effect of Ero1α was investigated using C57BL/6J mice, the HT22 cells and primary rat neurons. C57BL/6J mice were modeled in a hypoxic chamber for 4 weeks. Behavioral tests were then carried out to test cognitive functions, including the Morris water maze and fear conditioning test. Proteomics showed that Ero1α distinctly upregulated compared with normoxia group and verified using western blotting. Flow cytometry and immunofluorescence were used to analyze the neuroprotective effect of inhibitor EN460 of Ero1α in the HT22 cells. In C57BL/6J mice, hypoxia significantly caused cognitive decline. Brain slice staining results were also used to confirm this effect. Western blot analysis demonstrated that Ero1α, ERS-associated proteins and apoptosis-associated proteins significantly increased in the hypoxia treated groups, further proliferation-related marker protein decreased. EN460, a selective endoplasmic reticulum oxidation 1 (ERO1) inhibitor, counteracted neuronal apoptosis and ameliorated neuronal cell proliferation in the HT22 cells. Taken together, our data indicate that hypoxia induces cognitive impairment, at least in part, by upregulating Ero1α which contributes to neuronal apoptosis through ERS signaling pathway, providing preliminary experimental evidence that the Ero1α is a promising therapeutic target in hypoxia-induced cognitive deficits.