IRE1α-XBP1 Affects the Mitochondrial Function of Aβ25–35-Treated SH-SY5Y Cells by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes

• DOI: 10.3389/fncel.2021.614556
• Publication Date: 2021-03-25T05:39:54Z
• Authors: Bingcong Chu; Maoyu Li; Xi Cao; Rulong Li; Suqin Jin; Hui Yang; Linlin Xu; Ping Wang; Jianzhong Bi
• Keywords: XBP1; VDAC1; SH-SY5Y

Background: Neurotoxicity induced by the amyloid beta (Aβ) peptide is one of most important pathological mechanisms Alzheimer's disease (AD). Activation adaptive IRE1α-XBP1 pathway contributes to pathogenesis AD, making it a potential target for AD therapeutics. However, mechanism involvement in unclear. We, therefore, investigated effect axis an vitro model and explored its mechanism. Methods: The human neuroblastoma cell line, SH-SY5Y, was used. Cells were treated with Aβ25–35, or without 4μ8c, inhibitor IRE1α. collected analyzed Western blotting, quantitative real-time PCR, electron microscopy, fluorescence calcium imaging, other biochemical assays. Results: Aβ-exposed SH-SY5Y cells showed increased expression XBP1s p-IRE1α. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) imaging analysis that IRE1α inhibitor, reduced Aβ-induced cytotoxicity. Increased levels ATP, restoration mitochondrial membrane potential, decreased production reactive oxygen species after Aβ treatment presence 4μ8c inhibiting effectively mitigated dysfunction cells. Furthermore, interaction IP3R, Grp75, vdac1 led endoplasmic reticulum (ER)–mitochondria association, malfunction mitochondria-associated ER-membranes (MAMs), dysfunction. These deficits rescued axis. Conclusion: findings demonstrate induces activation axis, which may aggravate cytotoxicity impairment targeting MAMs. Inhibition provides protection against injury may, be new strategy.