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

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, A?₁ _- 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 IRE1?-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-IRE1? and associated apoptosis in SH-SY5Y cells, suggesting that ASK1 is essential for the assembly and function of the proapoptotic kinase activity of the IRE1? signalosome. In summary, ER stress and ASK1-JNK1/2 signaling play causal roles in DICD development, which has crosstalk through the formation of the IRE1?-TRAF2-ASK1 complex.

SUBMITTER: Wu Y

PROVIDER: S-EPMC7379134 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wu Yanqing Y Yuan Yuan Y Wu Chengbiao C Jiang Ting T Wang Beini B Xiong Jun J Zheng Peipei P Li Yiyang Y Xu Jingyu J Xu Ke K Liu Yaqian Y Li Xiaokun X Xiao Jian J

Frontiers in cell and developmental biology 20200717

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 ...[more]

PMID: 32766246

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Project description:The prevalence of diabetes-associated cognitive dysfunction (DACD) has increased to 13.5%. Dementia, as the most severe DACD, is the second leading cause of death in patients with diabetes mellitus. Hence, the potential mechanisms of DACD for slowing or halting its progression need to be urgently explored. Given that the sigma-1 receptor (Sig-1R), a chaperone protein located in the endoplasmic reticulum (ER)-mitochondrion contact membranes to regulate ER stress (ERS), is associated with cognitive outcomes in neurodegenerative diseases, this study aimed to investigate the role of astrocytic Sig-1R in DACD and its underlying mechanism. Here, we examined the levels of ERS and complement component 3/3a (C3/C3a) from primary astrocytes with different concentrations of glucose and treatment. Subsequently, HT22 neurons were cultured in different astrocyte-conditioned medium, and the expression of synaptic proteins was detected. We constructed type 1 diabetes mellitus (T1DM) model to evaluate the astrocytic Sig-1R mechanism on synapse and cognitive function changes. In vitro, high glucose concentration downregulated Sig-1R and aggravated ERS in astrocytes, resulting in synapse deficits. PRE-084, a high-affinity and selective Sig-1R agonist, inhibited astrocytic ERS and complement cascades and restored synaptic damage, while the Sig-1R antagonist displayed the opposite results. Moreover, C3a receptor antagonist (C3aRA) could mimic the effect of PRE-084 and exerted neuroprotective effects. In vivo, PRE-084 substantially reduced ER-mitochondrion contact, activation of ERS, and C3/C3a secretion in mice with T1DM. Additionally, the synaptic loss and neurobehavioral dysfunction of mice with T1DM were less pronounced in both the PRE-084 and C3aRA treatment groups. These findings demonstrated that Sig-1R activation reduced the astrocytic ER-mitochondrion contact, ERS activation, and complement-mediated synaptic damage in T1DM. This study suggested the mechanisms and potential therapeutic approaches for treating DACD.

Dataset Information

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

Publications

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

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