The neuroprotection of liraglutide on diabetic cognitive deficits is associated with improved hippocampal synapses and inhibited neuronal apoptosis

Yan, Wenhui; Pang, Miao; Yu, Yang; Gou, Xin; Si, Peiru; Zhawatibai, Alina; Zhang, Yutong; Zhang, Meng; Guo, Tingli; Yi, Xinyao; Chen, Lina

doi:10.1016/j.lfs.2019.116566

Cited by 51 publications

(38 citation statements)

References 60 publications

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“…Consistently, we have previously found that neuronal injury and cognitive impairment are prominent at 8 weeks following BCCAO [18]. Similarly, studies also found that STZ-induced DM could aggravate neuronal apoptosis and cognitive dysfunction in rodents [31]. In our present Morris water maze task, spatial learning and memory impairment were more pronounced in the DM-CCH group than those in the CCH group at 8 weeks post-surgery, as indicated by an increase in escape latency, fewer crossings over the original platform and less time spent in the target quadrant.…”

Section: Discussionsupporting

confidence: 86%

TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

Zhang

Liu

Zheng

et al. 2020

J Neuroinflammation

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Background: Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown. Methods:To investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively.Results: Cognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent proinflammatory mediator production under high glucose and hypoxia condition.Conclusions: These results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH.

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Section: Discussionsupporting

confidence: 86%

TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

Zhang

Liu

Zheng

et al. 2020

J Neuroinflammation

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“…These studies indicate that independent of ER stress, IRE1α exerts its proapoptotic effect by activating the ASK1-JNK1/2 pathway, supporting the hypothesis that IRE1α activity and ASK1 pathway activation has a reciprocal causal relationship during DICD. Additionally, diabetes-induced oxidative stress in the hippocampus of rats has been previously reported as a factor that contributes to cognitive dysfunction (Wang et al, 2010;Tabatabaei et al, 2017;Farbood et al, 2019) with evidence of synaptic damage (Fukui et al, 2001(Fukui et al, , 2002 and excessive neuronal apoptosis (Farbood et al, 2019;Nazarnezhad et al, 2019;Yan et al, 2019). The ASK1-JNK1/2 pathway, the important downstream of oxidative stress, may be the major mechanism for oxidative stress-mediated apoptosis during DICD, suggesting that cellular stress does not independently affect DICD development.…”

Section: Discussionmentioning

confidence: 99%

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

Yuan

et al. 2020

Front. Cell Dev. Biol.

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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, Aβ 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 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.

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“…CCH plays a pivotal role in the progression of cognitive impairments in VaD, as it can induce neuroin ammation, decrease energy supplementation, contribute to neuronal injury, and impair memory [18,49,50] . Importantly, a previous study has demonstrated that diabetes aggravates neuronal apoptosis and accelerates cognitive dysfunction [51] . In our present study, in the MWM, the DM/CCH group exhibited impairments in spatial learning and memory, as revealed by a prolonged escape latency, decreased number of crossings over the original platform location, and less time spent in the target quadrant; these ndings are consistent with those of previous reports [11,52,53] .…”

Section: Discussionmentioning

confidence: 99%

Curcumin Protects Against Cognitive Impairments in a Rat Model of Chronic Cerebral Hypoperfusion Combined with Diabetes Mellitus by Suppressing Neuroinflammation, Apoptosis, and Pyroptosis

Zheng

Zhang

Zhao

et al. 2020

Preprint

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BackgroundChronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown.MethodsRats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo. After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro. ResultsCurcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis.ConclusionsTaken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.

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The neuroprotection of liraglutide on diabetic cognitive deficits is associated with improved hippocampal synapses and inhibited neuronal apoptosis

Cited by 51 publications

References 60 publications

TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

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

Curcumin Protects Against Cognitive Impairments in a Rat Model of Chronic Cerebral Hypoperfusion Combined with Diabetes Mellitus by Suppressing Neuroinflammation, Apoptosis, and Pyroptosis

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