Aβ1-42 induces cell damage via RAGE-dependent endoplasmic reticulum stress in bEnd.3 cells

Highlights: • ERS involved in Aβ_1-42-resulted TJ disruption in endothelial cells. • Activation of ERS by Aβ_1-42 is mediated by RAGE in endothelial cells. • Aβ_1-42 induced endothelial cells damage and TJ disruption though RAGE-dependence ERS. Blood-brain barrier (BBB) breakdown has been determined to play a critical role in the pathogenesis of Alzheimer's disease (AD). However, the underlying mechanisms of BBB disruption in AD remain unclear. Our previous study suggested that the receptor for advanced glycation end-products (RAGE) functioned as a signal transduction receptor in Aβ_1–42-induced damage in endothelial cells. In our present study, we revealed that RAGE-mediated endoplasmic reticulum stress (ERS) is essential for Aβ-induced endothelial cell damage. Here, we found that Aβ_1–42 activated ERS by upregulation of Grp78, xbp-1 and CHOP in endothelial cells and that Aβ_1–42-resulted lesions, including the upregulations of caspase-12 and caspase-3, the augment of bax/bcl-2 ratio, and the downregulations of ZO-1 and Occludin in bEnd.3 cells, were ameliorated by the pretreatment of salubrinal, an ERS inhibitor. Furthermore, the expressions of Grp78, xbp-1 and CHOP induced by Aβ_1–42 were blocked by transfection of RAGE small interfering RNA (siRNA), which indicated that Aβ_1–42 activated ERS in a RAGE-dependent manner. Additionally, bEnd.3 cells transfected with RAGE siRNA showed lower expressions of caspase-12 and caspase-3, decreased bax/bcl-2 ratio, and higher expressions of ZO-1 and Occludin following Aβ1-42 treatment, comparing to control cells. In conclusion, our data demonstrated that Aβ_1–42 induced endothelial cells damage via activation of ERS in a RAGE-dependent manner.