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

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

doi:10.3389/fcell.2020.00602

Abstract

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.

Highlights

Diabetes is a serious, chronic metabolic disorder that adversely affects multiple organs due to its long-term complications, and the brain is one of the major targets, which results in diabetic encephalopathy (DE) (Mijnhout et al, 2006)
Cleaved caspase-3 level in the hippocampus of db/db mice were significantly increased compared with that in the db/m mice (Figure 3D). These results suggest that diabetes induces excessive neuronal apoptosis by triggering the mitochondrial pathway
We examined the expression of endoplasmic reticulum (ER) stress markers in the hippocampus and found that the protein levels of p-inositol-requiring enzyme 1α (IRE1α), p-protein kinase RNA-like ER kinase (PERK), p-eIF2α, and CHOP were significantly increased in the hippocampus of db/db mice when compared with those in db/m mice (Figures 4A–E)

Summary

Introduction

Chronic metabolic disorder that adversely affects multiple organs due to its long-term complications, and the brain is one of the major targets, which results in diabetic encephalopathy (DE) (Mijnhout et al, 2006). Diabetes-induced cognitive decline (DICD) is one of the most common types of DE. The duration of diabetes and level of hyperglycemia are positively correlated with the level of cognitive dysfunction (Li et al, 2003; de la Monte and Wands, 2008). The hippocampus, which is highly susceptible to hyperglycemia, is essential for short-term memory, learning, executive ability, and attention of brain. The cornu ammon (CA1) region in the hippocampus is most closely related to cognitive function, and considered as a specific target for the changes related to cognitive function in DICD studies (Di Mario et al, 1995; Sun et al, 2014). DICD has attracted extensive attention, the molecular mechanisms underlying it are not well understood

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