Epigallocatechin Gallate Reduces Amyloid β‐Induced Neurotoxicity via Inhibiting Endoplasmic Reticulum Stress‐Mediated Apoptosis

Scope We investigated the role of endoplasmic reticulum (ER) stress in the protective effects of EGCG against the neuronal apoptosis in Aβ1‐42‐induced SH‐SY5Y cells and APP/PS1 transgenic mice. Methods and results Cell viability (CCK8 assay), flow cytometry, Hoechst 33258 staining, immunohistochemistry, transmission electron microscopy (TEM), and western blotting were used. EGCG prevented Aβ1‐42‐induced toxicity in SH‐SY5Y cells, increased cell viability, and decreased apoptosis in a dose‐dependent manner. In a subsequent mechanism study, it was found that this effect contributed to the down‐regulation of GRP78, CHOP, cleaved‐caspase‐12 and ‐3. Moreover, EGCG also reduced the cytotoxicity induced by tunicamycin (TM) and thapsigargin (TG), two ER stress activators. Consistent with the in vitro study, EGCG inhibited neuronal apoptosis in the cortex of APP/PS1 transgenic mice, with the mitigation of ER abnormal ultrastructural swelling and the downregulation of ER‐stress‐associated proteins. Conclusion These results indicate that EGCG attenuates the neurotoxicity in Alzheimer's disease (AD) via a novel mechanism that involves inhibition of ER‐stress‐associated neuronal apoptosis in vitro and in vivo, suggesting the tremendous potential of EGCG for use in a nutritional preventive strategy against AD. Epigallocatechin gallate (EGCG) inhibits endoplasmic reticulum (ER)‐stress‐associated neuronal apoptosis in Aβ‐treated SH‐SY5Y cells in vitro and in APP/PS1 mice in vivo, suggesting that inhibition of ER‐stress‐associated neuronal apoptosis contributed to the anti‐AD mechanisms of EGCG treatment.