AUTHOR=Wu Yanqing , Yuan Yuan , Wu Chengbiao , Jiang Ting , Wang Beini , Xiong Jun , Zheng Peipei , Li Yiyang , Xu Jingyu , Xu Ke , Liu Yaqian , Li Xiaokun , Xiao Jian 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 8 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00602

DOI=10.3389/fcell.2020.00602

ISSN=2296-634X

ABSTRACT=Diabetes significantly induces cognitive dysfunction. Neuronal apoptosis is the main caused event for 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 has not yet been elucidated. In this study, we used db/db mice as 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 largely 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 IRE1α-TRAF2-ASK1 complex.