A beta(1-42) induces cell damage via RAGE-dependent endoplasmic reticulum stress in bEnd.3 cells

作者：Chen, Wenjing; Chan, Yuanjin; Wan, Wenbin; Li, Yaming^*; Zhang, Chunyan^*

来源：Experimental Cell Research, 2018, 362(1): 83-89.

DOI：10.1016/j.yexcr.2017.11.005

• Alzheimer's disease
• Blood-brain barrier
• Beta-amyloid
• The receptor for advanced glycation end products
• Endoplasmic reticulum stress

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 A beta(1-42)-induced damage in endothelial cells. In our present study, we revealed that RAGE-mediated endoplasmic reticulum stress (ERS) is essential for A beta-induced endothelial cell damage. Here, we found that A beta(1-42) activated ERS by upregulation of Grp78, xbp-1 and CHOP in endothelial cells and that A beta(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 salu-brinal, an ERS inhibitor. Furthermore, the expressions of Grp78, xbp-1 and CHOP induced by A beta(1-42) were blocked by transfection of RAGE small interfering RNA (siRNA), which indicated that A beta(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 A beta(1-42) treatment, comparing to control cells. In conclusion, our data demonstrated that A beta(1-42) induced endothelial cells damage via activation of ERS in a RAGE-dependent manner.

• 出版日期2018-1-1
• 单位同济大学; 复旦大学