Background Alzheimer's disease(AD)is a neurodegenerative disorder that affects the central nervous system.Silent information regulator sirtuin 1(SIRT1)may deacetylate and suppress forkhead box O(FOXO)activities to...Background Alzheimer's disease(AD)is a neurodegenerative disorder that affects the central nervous system.Silent information regulator sirtuin 1(SIRT1)may deacetylate and suppress forkhead box O(FOXO)activities to promote neuronal survival.FOXO1 is involved in the regulation of metabolism,senescence,stress response,and apoptosis.Moreover,endoplasmic reticulum stress(ERS)mediates cell apoptosis.Therefore,this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis in amyloid precursor protein/presenilin 1(APP/PS1)transgenic mice.MethodsWe used APP/PS1 transgenic mice to construct an in vivo AD model.Additionally,we usedβ-amyloid(Aβ)-incubated HT22 cells and primary neurons(PNs)for in vitro analyses.Cognitive function was assessed using novel object recognition,the Morris water maze,and fear conditioning.Discrepancies between wild-type(WT)and APP/PS1 transgenic mice were evaluated using an unpaired t test.In addition,one-way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups,followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.ResultsThe expression of SIRT1 was downregulated(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p=0.002;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.001;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),whereas FOXO1 acetylation was upregulated both in vivo and in vitro(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p<0.001;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.004;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),leading to cognitive dysfunction,Aβplaque deposition,and neuronal apoptosis.Quercetin,a SIRT1 agonist,reversed these changes(For SIRT1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p=0.014;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.003;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ1−42+Quercetin,n=3,p=0.014.For ac-FOXO1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p<0.001;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.023;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ_(1−42)+Quercetin,n=3,p=0.003).However,the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice(ac-FOXO1:Quercetin-treated APP/PS1 mice vs.AS1842856-treated APP/PS1 mice,n=3,p<0.001).Quercetin counteracted FOXO1 acetylation and ERS-mediated apoptosis.In contrast,AS1842856 promoted these processes in vivo and in vitro.Conclusion Our findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis.展开更多
Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Here...Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Herein,a mouse model of CKD was established using conventional 5/6 nephrectomy.We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods:Cognitive behavior was assessed using the Morris water maze,novel object recognition test,and fear conditioning test.Further experiments were also conducted to investigate the underlying molecular mechanisms.Results:Our clinical data revealed a decrease in cognitive function among patients with CKD,accompanied by elevated plasma levels of pro-inflammatory cytokines.A positive correlation between cytokine concentrations and serum creatinine levels,as well as a significant positive correlation with cognitive dysfunction,were observed.Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice.Furthermore,20 mg/mL interleukin-6(IL-6)significantly decreased HT22 cell activity in vitro.Further,HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4(TLR4)and myeloid differentiation primary response gene 88(MyD88),thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis.The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus.TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells.TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites,thus ameliorated cognitive impairment.Conclusion:These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD,ultimately culminate in cognitive impairment.展开更多
基金International Clinical Exchange Program of Health Commission of Zhejiang ProvinceNational Natural Science Foundation of China,Grant/Award Number:31900685+3 种基金Zhejiang Province Natural Science Foundation,Grant/Award Numbers:LTGY24H050004,LTGY23H050003Wenzhou Municipal Science and Technology Bureau of China,Grant/Award Number:Y2023065School Level Scientific Research Project of Wenzhou Medical University,Grant/Award Numbers:XY2022007,wyx2023101049Medical Innovation Discipline of Zhejiang Province,Grant/Award Number:Y2015。
文摘Background Alzheimer's disease(AD)is a neurodegenerative disorder that affects the central nervous system.Silent information regulator sirtuin 1(SIRT1)may deacetylate and suppress forkhead box O(FOXO)activities to promote neuronal survival.FOXO1 is involved in the regulation of metabolism,senescence,stress response,and apoptosis.Moreover,endoplasmic reticulum stress(ERS)mediates cell apoptosis.Therefore,this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis in amyloid precursor protein/presenilin 1(APP/PS1)transgenic mice.MethodsWe used APP/PS1 transgenic mice to construct an in vivo AD model.Additionally,we usedβ-amyloid(Aβ)-incubated HT22 cells and primary neurons(PNs)for in vitro analyses.Cognitive function was assessed using novel object recognition,the Morris water maze,and fear conditioning.Discrepancies between wild-type(WT)and APP/PS1 transgenic mice were evaluated using an unpaired t test.In addition,one-way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups,followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.ResultsThe expression of SIRT1 was downregulated(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p=0.002;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.001;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),whereas FOXO1 acetylation was upregulated both in vivo and in vitro(in animal experiments,WT mice vs.APP/PS1 mice,n=3,p<0.001;in cell experiments,HT22 cells vs.HT22 cells+Aβ_(1−42),n=3,p=0.004;primary neurons vs.primary neurons+Aβ_(1−42),n=3,p<0.001),leading to cognitive dysfunction,Aβplaque deposition,and neuronal apoptosis.Quercetin,a SIRT1 agonist,reversed these changes(For SIRT1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p=0.014;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.003;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ1−42+Quercetin,n=3,p=0.014.For ac-FOXO1,APP/PS1 mice vs.Quercetin-treated APP/PS1 mice,n=3,p<0.001;HT22 cells+Aβ_(1−42)vs.HT22 cells+Aβ_(1−42)+Quercetin,n=3,p=0.023;primary neurons+Aβ_(1−42)vs.primary neurons+Aβ_(1−42)+Quercetin,n=3,p=0.003).However,the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice(ac-FOXO1:Quercetin-treated APP/PS1 mice vs.AS1842856-treated APP/PS1 mice,n=3,p<0.001).Quercetin counteracted FOXO1 acetylation and ERS-mediated apoptosis.In contrast,AS1842856 promoted these processes in vivo and in vitro.Conclusion Our findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS-mediated apoptosis.
基金Zhejiang Provincial Outstanding Youth Science Foundation,Grant/Award Numbers:2023C35009,LTGY23H050003,LTGY24H050004Scienceand Technology Plan Project of Wenzhou Municipality,Grant/Award Numbers:Y2020024,Y20210162,Y2023065Wenzhou Medical University,Grant/Award Number:XY2022007。
文摘Backgrounds:Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease(CKD)leads to cognitive impairment.However,the underlying mechanism requires further investigation.Herein,a mouse model of CKD was established using conventional 5/6 nephrectomy.We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods:Cognitive behavior was assessed using the Morris water maze,novel object recognition test,and fear conditioning test.Further experiments were also conducted to investigate the underlying molecular mechanisms.Results:Our clinical data revealed a decrease in cognitive function among patients with CKD,accompanied by elevated plasma levels of pro-inflammatory cytokines.A positive correlation between cytokine concentrations and serum creatinine levels,as well as a significant positive correlation with cognitive dysfunction,were observed.Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice.Furthermore,20 mg/mL interleukin-6(IL-6)significantly decreased HT22 cell activity in vitro.Further,HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4(TLR4)and myeloid differentiation primary response gene 88(MyD88),thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis.The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus.TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells.TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites,thus ameliorated cognitive impairment.Conclusion:These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD,ultimately culminate in cognitive impairment.
