Abstract
Background: Neurotoxicity induced by the amyloid beta (Aβ) peptide is one of the most important pathological mechanisms of Alzheimer's disease (AD). Activation of the adaptive IRE1α-XBP1 pathway contributes to the pathogenesis of AD, making it a potential target for AD therapeutics. However, the mechanism of IRE1α-XBP1 pathway involvement in AD is unclear. We, therefore, investigated the effect of the IRE1α-XBP1 axis in an in vitro AD model and explored its potential mechanism.Methods: The human neuroblastoma cell line, SH-SY5Y, was used. Cells were treated with Aβ25–35, with or without 4μ8c, an inhibitor of IRE1α. Cells were collected and analyzed by Western blotting, quantitative real-time PCR, electron microscopy, fluorescence microscopy, calcium imaging, and other biochemical assays.Results: Aβ-exposed SH-SY5Y cells showed an increased expression of XBP1s and p-IRE1α. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and calcium imaging analysis showed that the IRE1α inhibitor, 4μ8c, reduced Aβ-induced cytotoxicity. Increased levels of ATP, restoration of mitochondrial membrane potential, and decreased production of mitochondrial reactive oxygen species after Aβ treatment in the presence of 4μ8c showed that inhibiting the IRE1α-XBP1 axis effectively mitigated Aβ-induced mitochondrial dysfunction in SH-SY5Y cells. Furthermore, Aβ treatment increased the expression and interaction of IP3R, Grp75, and vdac1 and led to an increased endoplasmic reticulum (ER)–mitochondria association, malfunction of mitochondria-associated ER-membranes (MAMs), and mitochondrial dysfunction. These deficits were rescued by inhibiting the IRE1α-XBP1 axis.Conclusion: These findings demonstrate that Aβ peptide induces the activation of the IRE1α-XBP1 axis, which may aggravate cytotoxicity and mitochondrial impairment in SH-SY5Y cells by targeting MAMs. Inhibition of the IRE1α-XBP1 axis provides the protection against Aβ-induced injury in SH-SY5Y cells and may, therefore, be a new treatment strategy.
Highlights
Alzheimer’s disease (AD), the most common cause of dementia, is a chronic and progressive neurodegenerative disease
To investigate whether the Inositolrequiring enzyme 1α (IRE1α) signaling pathway is activated in SH-SY5Y cells after Aβ25–35 exposure, we determined the activation of IRE1α by measuring IRE1α phosphorylation and expression of spliced X-box binding protein 1 (XBP1), a downstream factor of IRE1α
To determine whether IRE1α-XBP1 is involved in Aβ-induced death of SH-SY5Y cells, we blocked IRE1α with various inhibitors, such as 4μ8C, STF-083010, and MKC-3946 (Zhang et al, 2014; Li et al, 2019)
Summary
Alzheimer’s disease (AD), the most common cause of dementia, is a chronic and progressive neurodegenerative disease. Aβ peptides are produced by the proteolytic cleavage of the amyloid precursor protein (APP) by β-secretase and γ-secretase cleavage (Thinakaran and Koo, 2008). There is evidence that the activation of IRE1α aggravates the histopathological progress of AD (Duran-Aniotz et al, 2017). These studies suggest that IRE1α-XBP1 signaling may participate in causing AD; its specific role in the disease remains poorly defined. Neurotoxicity induced by the amyloid beta (Aβ) peptide is one of the most important pathological mechanisms of Alzheimer’s disease (AD). Activation of the adaptive IRE1α-XBP1 pathway contributes to the pathogenesis of AD, making it a potential target for AD therapeutics. We investigated the effect of the IRE1α-XBP1 axis in an in vitro AD model and explored its potential mechanism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
