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  • Decreasing GSK activity has therapeutic benefits in animal

    2021-09-13

    Decreasing GSK-3β activity has therapeutic benefits in animal model of colitis [45] and traumatic ubiquitin proteasome system injury [46] and ischemia/reperfusion injury [47,48]. In brain, activation of GSK-3β promotes Aβ toxicity by elevating APP expression and its amyloidogenic cleavage, and by dysregulating Aβ clearance mechanisms [49]. In HFFD fed mice, GSK-3β is active which might have triggered amyloid deposition. As a potential therapy for injurious stimuli induced by HFFD the beneficial effects of the GSK-3β inhibitor IMX has been investigated. IMX has been shown to inhibit GSK-3β on binding to the catalytic site, by competing with ATP [50]. IMX inhibits Aβ-induced neurotoxicity in neuroblastoma cell lines [51] and stimulate the expression of the Aβ degrading enzymes, IDE and neprilysin in APP/PS1 mice [22]. IMX has been proposed to be a neuroprotective agent however the efficacy of IMX on Aβ-driven gliopathology and neuroinflammation induced by HFFD has not been studied so far. An intriguing finding of the present study is the effect of IMX on amyloid clearance. Our results reveal that IMX treatment could potentiate clearance of Aβ plaques induced by HFFD and this effect has been well correlated with potent inhibitory effect on GSK-3β. Nevertheless, the influence of IMX towards Aβ metabolism warrant future studies in this HFFD-model. Previous studies demonstrate that IMX suppresses LPS-stimulated microglial cells [52] and attenuate astocytic/microglial activation in mouse model of AD [22]. In our study, IMX administration significantly decreased the protein expression of the astrocyte intermediate filament protein GFAP and the microglial surface maker CD-68. The results signify that IMX could suppress gliosis, and we speculate IMX may possibly reword amyloid clearance mechanisms. Researchers emphasize critical roles for GSK-3β in facilitating NF-κB activation, as well as the induction of NF-κB targeted pro-inflammatory molecules [46,53]. GSK-3β activates NF-κB in LPS-stimulated RAW264.7 mouse macrophage cells [54] and positively regulates expression of pro-inflammatory genes in LPS-stimulated human monocytic cells and mouse hippocampal slice culture [52,55]. In order to ascertain the modulation of IKK-β/NF-κB signaling by HFFD and IMX, we assessed the phosphorylation status of the serine/threonine kinase IKK-β and protein expression of NF-κB p65 in nuclear extracts. IKK-β/NF-κB is a pluripotent master switch play role in classical immune response [56]. The prototypical NF-κB heterodimer consists of p50 and p65 subunits, which are sequestered in the cytoplasm through its association with IκB-α. Phosphorylation and activation of the stress kinase IKK-β phosphorylates its substrate IκB-α, which undergoes rapid ubiquitination and degradation. The dissociation of IκB-α allows NF-κB p60 and p65 to enter nucleus, where it binds to specific promoters to transcribe its downstream effectors like TNF-α, IL-6 and COX-2 [57]. In our study, HFFD feeding elicited activation of IKK-β by phosphorylation and orchestrated nuclear translocation of NF-κB p65 in brain. Our results are consistent with a previous study which found that overnutrition can cause atypical activation of hypothalamic IKK-β/NF-κB [58]. The rise in immunopositive cells for TNF-α and IL-6 found in HFFD mice can be related to NF-κB activation as a sequel of amyloid deposition as reported previously [[59], [60], [61]]. Our results support previous observation documented that accumulation of Aβ-peptides promotes nuclear translocation of NF-κB and contributes to the generation of pro-inflammatory molecules [62]. IMX has been shown to inhibit NF-κB activation and JNK signaling to suppress the production of inflammatory mediators in LPS-treated RAW264.7 cells [63]. Similarly, treating HFFD mice with IMX reduced the levels of NF-κB p65 in nuclear extracts, and immunofluorescence images clearly depict cytoplasmic localization. Moreover, IMX treatment significantly decreased the protein expression of TNF-α and IL-6, which authenticates blockade of NF-κB signaling. IMX may suppress aberrant NF-κB signaling via IKK-β inactivation as revealed in the present study. The antiinflammatory effects of IMX and alleviation of metabolic perturbations in peripheral tissues of mice has been demonstrated [64,23]. IMX treatment was found to exert anti-inflammatory effect at peripheral tissues, liver and kidney as well (data not shown).