The Reciprocal Causation of the ASK1-JNK1/2 Pathway and Endoplasmic Reticulum Stress in Diabetes-Induced Cognitive Decline

Frontiers in Cell and Developmental Biology

Chengbiao Wu¹  Yanqing Wu²  Ting Jiang²  Yaqian Liu²  Yuan Yuan²  Yiyang Li²  Beini Wang²  Jian Xiao²  Xiaokun Li²  Jun Xiong²  Peipei Zheng²  Ke Xu³  Jingyu Xu³ 

[1] Clinical Research Center, Affiate Xiangshang Hospital, Wenzhou Medical University, Wenzhou, China;Research Units of Clinical Translation of Cell Growth Factors and Diseases Research of Chinese Academy of Medical Science, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China;The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, China;

关键词: diabetes-induced cognitive decline (DICD);    hippocampus;    neuronal apoptosis;    apoptosis signal-regulating kinase 1 (ASK1);    endoplasmic reticulum (ER) stress;   

DOI  :  10.3389/fcell.2020.00602

来源: DOAJ

【 摘 要 】

Diabetes significantly induces cognitive dysfunction. Neuronal apoptosis is the main cause of diabetes-induced cognitive decline (DICD). Apoptosis signal-regulating kinase 1 (ASK1) and endoplasmic reticulum (ER) stress are remarkably activated by diabetes. The role and relationship of ASK1-JNK1/2 signaling and ER stress in DICD have not yet been elucidated. In this study, we used db/db mice as the DICD animal model and confirmed that db/db mice displayed cognitive decline with inferior learning and memory function. Diabetes significantly induced morphological and structural changes, excessive neuronal apoptosis, Aβ1–42 large deposition, and synaptic dysfunction in the hippocampus. Mechanistic studies found that diabetes significantly triggered ASK1-JNK1/2 signaling activation and increased ER stress in the hippocampus. Moreover, diabetes enhanced the formation of the IRE1α–TRAF2–ASK1 complex, which promotes the crosstalk of ER stress and the ASK1-JNK1/2 pathway during DICD. Furthermore, 4-PBA treatment blocked high glucose (HG)-induced ASK1-JNK1/2 signaling activation, and excessive apoptosis in vitro. Inhibiting ASK1 via siRNA remarkably ameliorated the HG-induced increase in p-IRE1α and associated apoptosis in SH-SY5Y cells, suggesting that ASK1 is essential for the assembly and function of the proapoptotic kinase activity of the IRE1α signalosome. In summary, ER stress and ASK1-JNK1/2 signaling play causal roles in DICD development, which has crosstalk through the formation of the IRE1α–TRAF2–ASK1 complex.

【 授权许可】

Unknown