Background:Neuroinflammation and accumulation ofβ-amyloid(Aβ)play a significant role in the onset and progression of Alzheimer’s disease(AD).Our previous study demonstrated that signal transducer and activator of t...Background:Neuroinflammation and accumulation ofβ-amyloid(Aβ)play a significant role in the onset and progression of Alzheimer’s disease(AD).Our previous study demonstrated that signal transducer and activator of transcription-3(STAT3)plays a major role in neuroinflammation and amyloidogenesis.Methods:In the present study,we investigated the inhibitory effect of bee venom phospholipase A2(bvPLA2)on memory deficiency in Tg2576 mice,which demonstrate genetic characteristics of AD and the mechanism of its action at the cellular and animal level.For in vivo study,we examined the effect of bvPLA2 on improving memory by conducting several behavioral tests with the administration of bvPLA2(1 mg/kg)to Tg2576 mice.For in vitro study,we examined the effect of bvPLA2 on amyloidogenesis and neuroinflammation by treating bvPLA2 on LPSactivated BV2 cells.Results:We found that bvPLA2 alleviated memory impairment in Tg2576 mice,as demonstrated in the behavioral tests assessing memory.In the bvPLA2-treated group,Aβ,amyloid precursor protein(APP),and β-secretase 1(BACE1)levels and β-secretase activity were significantly decreased.Expression of pro-inflammatory cytokines and inflammation-related proteins decreased in the brain of bvPLA2-treated group,whereas anti-inflammatory cytokines increased.In addition,bvPLA2 reduced STAT3 phosphorylation in the brains of the bvPLA2-treated group.At the cellular level,bvPLA2 inhibits production of nitric oxide,pro-inflammatory cytokines,and inflammation-related proteins including p-STAT3.Additionally,bvPLA2 inhibits the production of Aβin cultured BV-2 cells.Results from the docking experiment,pull-down assay,and the luciferase assay show that bvPLA2 directly binds STAT3 and,thus,regulates gene expression levels.Moreover,when the STAT3 inhibitor and bvPLA2 were administered together,the anti-amyloidogenic and anti-inflammatory effects were further enhanced than when they were administered alone.Conclusion:These results suggest that bvPLA2 could restore memory by inhibiting the accumulation of Aβ and inflammatory responses via blockage of STAT3 activity.展开更多
Inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD),has been increasingly associated with the progression of neurodegenerative disorders,particularly Alzheimer’s disease(AD).Emerg...Inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD),has been increasingly associated with the progression of neurodegenerative disorders,particularly Alzheimer’s disease(AD).Emerging data from population-based meta-analyses and in vivo experimental models demonstrate that systemic inflammation associated with IBD exacerbates disruption of the gut-brain axis(GBA).This disruption promotes the deposition of amyloid-β(Aβ)plaques,and cognitive decline.Together,these effects contribute to the progression of AD.Chronic colitis,a hallmark of IBD,accelerates Aβpathology and induces cognitive impairment in transgenic mouse models,providing direct evidence of the detrimental effects of gut inflammation on neurodegeneration.Although numerous clinical and meta-analytical studies have examined the prevalence of AD in IBD patients,the molecular mechanisms underlying this association remain inadequately understood.In particular,the roles of immune regulation and GBA interactions require further investigation.This review aims to critically compile current evidence that elucidates the shared pathophysiological mechanisms underlying this association,such as chronic systemic inflammation,gut dysbiosis,and dysregulated immune responses.Although anti-inflammatory therapies,probiotics,and modulation of the gut microbiota have the potential to reduce the risk of AD and slow its progression,age-related gut inflammation and dysbiosis can aggravate AD pathology.This underscores the necessity for treatments that specifically target IBD-associated inflammation to limit AD progression.In addition,this review also meticulously examines how immune signaling and regulatory pathways in IBD,such as triggering receptor expression via myeloid cell receptor activation;NLRP3 inflammasome-driven inflammation;disrupted interleukin(IL)-1β,IL-6,and tumor necrosis factor-alpha(TNF-α)signaling;and elevated C-reactive protein levels,contribute to increased amyloidogenesis.This paper proposes a comprehensive framework for therapeutic strategies targeting IBD-related inflammation and elucidates their potential to attenuate the progression of AD.展开更多
Given the failure to develop disease-modifying therapies for Alzheimer’s disease(AD),strategies aiming at preventing or delaying the onset of the disease are being prioritized.While the debate regarding whether depre...Given the failure to develop disease-modifying therapies for Alzheimer’s disease(AD),strategies aiming at preventing or delaying the onset of the disease are being prioritized.While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on,a key determining factor may be the timing of depression onset in older adults.There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline.Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden,tau deposits and neurogenesis.In humans,studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors.Paroxetine,which has strong anticholinergic properties,was associated with increased mortality and mixed effects on amyloid and tau deposits in mice,as well as increased odds of developing AD in humans.Although most of the data regarding selective serotonin reuptake inhibitors is promising,findings should be interpreted cautiously because of notable methodological heterogeneity between studies.There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.展开更多
The synthesis of a promising brain imaging agent 4-[F-18]fluoro-4-deoxy-N-acetyl-1,3,6-tri-O-acetylglucosamine, 2, was successfully accomplished from commercially available N-acetyl glucosamine in 5 steps. The non-dec...The synthesis of a promising brain imaging agent 4-[F-18]fluoro-4-deoxy-N-acetyl-1,3,6-tri-O-acetylglucosamine, 2, was successfully accomplished from commercially available N-acetyl glucosamine in 5 steps. The non-decay corrected radiochemical yield and purity were found to be 31% ± 4% (n = 3) and >98% respectively. The total reaction time for radio labelling step was 50 min.展开更多
基金This work was supported by the National Research Foundation of Korea(NRF)grant funded by Korea government(MSIP)(No.MRC,2017R1A5A2015541)was supported by Korea Institute for Advancement of Technology(KIAT)as the research project for World Class 300 R&D(WC300 R&D,No.S2563418).
文摘Background:Neuroinflammation and accumulation ofβ-amyloid(Aβ)play a significant role in the onset and progression of Alzheimer’s disease(AD).Our previous study demonstrated that signal transducer and activator of transcription-3(STAT3)plays a major role in neuroinflammation and amyloidogenesis.Methods:In the present study,we investigated the inhibitory effect of bee venom phospholipase A2(bvPLA2)on memory deficiency in Tg2576 mice,which demonstrate genetic characteristics of AD and the mechanism of its action at the cellular and animal level.For in vivo study,we examined the effect of bvPLA2 on improving memory by conducting several behavioral tests with the administration of bvPLA2(1 mg/kg)to Tg2576 mice.For in vitro study,we examined the effect of bvPLA2 on amyloidogenesis and neuroinflammation by treating bvPLA2 on LPSactivated BV2 cells.Results:We found that bvPLA2 alleviated memory impairment in Tg2576 mice,as demonstrated in the behavioral tests assessing memory.In the bvPLA2-treated group,Aβ,amyloid precursor protein(APP),and β-secretase 1(BACE1)levels and β-secretase activity were significantly decreased.Expression of pro-inflammatory cytokines and inflammation-related proteins decreased in the brain of bvPLA2-treated group,whereas anti-inflammatory cytokines increased.In addition,bvPLA2 reduced STAT3 phosphorylation in the brains of the bvPLA2-treated group.At the cellular level,bvPLA2 inhibits production of nitric oxide,pro-inflammatory cytokines,and inflammation-related proteins including p-STAT3.Additionally,bvPLA2 inhibits the production of Aβin cultured BV-2 cells.Results from the docking experiment,pull-down assay,and the luciferase assay show that bvPLA2 directly binds STAT3 and,thus,regulates gene expression levels.Moreover,when the STAT3 inhibitor and bvPLA2 were administered together,the anti-amyloidogenic and anti-inflammatory effects were further enhanced than when they were administered alone.Conclusion:These results suggest that bvPLA2 could restore memory by inhibiting the accumulation of Aβ and inflammatory responses via blockage of STAT3 activity.
文摘Inflammatory bowel disease(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD),has been increasingly associated with the progression of neurodegenerative disorders,particularly Alzheimer’s disease(AD).Emerging data from population-based meta-analyses and in vivo experimental models demonstrate that systemic inflammation associated with IBD exacerbates disruption of the gut-brain axis(GBA).This disruption promotes the deposition of amyloid-β(Aβ)plaques,and cognitive decline.Together,these effects contribute to the progression of AD.Chronic colitis,a hallmark of IBD,accelerates Aβpathology and induces cognitive impairment in transgenic mouse models,providing direct evidence of the detrimental effects of gut inflammation on neurodegeneration.Although numerous clinical and meta-analytical studies have examined the prevalence of AD in IBD patients,the molecular mechanisms underlying this association remain inadequately understood.In particular,the roles of immune regulation and GBA interactions require further investigation.This review aims to critically compile current evidence that elucidates the shared pathophysiological mechanisms underlying this association,such as chronic systemic inflammation,gut dysbiosis,and dysregulated immune responses.Although anti-inflammatory therapies,probiotics,and modulation of the gut microbiota have the potential to reduce the risk of AD and slow its progression,age-related gut inflammation and dysbiosis can aggravate AD pathology.This underscores the necessity for treatments that specifically target IBD-associated inflammation to limit AD progression.In addition,this review also meticulously examines how immune signaling and regulatory pathways in IBD,such as triggering receptor expression via myeloid cell receptor activation;NLRP3 inflammasome-driven inflammation;disrupted interleukin(IL)-1β,IL-6,and tumor necrosis factor-alpha(TNF-α)signaling;and elevated C-reactive protein levels,contribute to increased amyloidogenesis.This paper proposes a comprehensive framework for therapeutic strategies targeting IBD-related inflammation and elucidates their potential to attenuate the progression of AD.
文摘Given the failure to develop disease-modifying therapies for Alzheimer’s disease(AD),strategies aiming at preventing or delaying the onset of the disease are being prioritized.While the debate regarding whether depression is an etiological risk factor or a prodrome of AD rages on,a key determining factor may be the timing of depression onset in older adults.There is increasing evidence that untreated early-onset depression is a risk factor and that late-onset depression may be a catalyst of cognitive decline.Data from animal studies have shown a beneficial impact of selective serotonin reuptake inhibitors on pathophysiological biomarkers of AD including amyloid burden,tau deposits and neurogenesis.In humans,studies focusing on subjects with a prior history of depression also showed a delay in the onset of AD in those treated with most selective serotonin reuptake inhibitors.Paroxetine,which has strong anticholinergic properties,was associated with increased mortality and mixed effects on amyloid and tau deposits in mice,as well as increased odds of developing AD in humans.Although most of the data regarding selective serotonin reuptake inhibitors is promising,findings should be interpreted cautiously because of notable methodological heterogeneity between studies.There is thus a need to conduct large scale randomized controlled trials with long follow up periods to clarify the dose-effect relationship of specific serotonergic antidepressants on AD prevention.
文摘The synthesis of a promising brain imaging agent 4-[F-18]fluoro-4-deoxy-N-acetyl-1,3,6-tri-O-acetylglucosamine, 2, was successfully accomplished from commercially available N-acetyl glucosamine in 5 steps. The non-decay corrected radiochemical yield and purity were found to be 31% ± 4% (n = 3) and >98% respectively. The total reaction time for radio labelling step was 50 min.
