Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo ag...Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo against Aβ. Our previous study found that hyperoside suppressed Aβ1-42-induced leakage of the BBB, however, the mechanism remains unclear. In this study, bEnd.3 cells were pretreated with 50, 200, or 500 μM hyperoside for 2 hours, and then exposed to Aβ1-42 for 24 hours. Cell viability was determined using 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide assay. Flow cytometry and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay were used to analyze cell apoptosis. Western blot assay was carried out to analyze expression levels of Bax, Bcl-2, cytochrome c, caspase-3, caspse-8, caspase-9, caspase-12, occludin, claudin-5, zonula occludens-1, matrix metalloproteinase-2（MMP-2）, and MMP-9. Exposure to Aβ1-42 alone remarkably induced bEnd.3 cell apoptosis; increased ratios of cleaved caspase-9/caspase-9, Bax/Bcl-2, cleav ed caspase-8/caspase-8, and cleaved caspase-12/caspase-12; increased expression of cytochrome c and activity of caspase-3; diminished levels of zonula occludens-1, claudin-5, and occludin; and increased levels of MMP-2 and MMP-9. However, hyperoside pretreatment reversed these changes in a dose-dependent manner. Our findings confirm that hyperoside alleviates fibrillar Aβ1-42-induced BBB disruption, thus offering a feasible therapeutic application in Alzheimer＇s disease.展开更多
Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxi...Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxicity partly via oxidative stress. In this study, we investigated the effect of crocetin on hippocampal HT22 cell death induced by Aβ1-42. Furthermore, to clarify the mechanism underlying the protective effects of crocetin against Aβ1-42- induced cell death, we measured reactive oxygen species (ROS) production by CM-H2DCFDA kit assay. Crocetin at 1 -10 μM protected HT22 cells against Aβ1-42-induced neuronal cell death and decreased ROS production increased by Aβ1-42. These results that crocetin has the potent neuroprotective effect against Aβ1-42-induced cytotoxicity in hippocampal cells by attenuating oxidative stress, suggest that crocetin may provide a useful therapeutic strategy against Aβ-related disorders.展开更多
BACKGROUND： The pharmacological actions of Panax notoginseng saponins （PNS） lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheime...BACKGROUND： The pharmacological actions of Panax notoginseng saponins （PNS） lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheimer＇s disease. OBJECTIVE： Using the Morris water maze, immunohistochemistry, real-time PCR and RT-PCR, this study aimed to measure improvement in spatial learning, memory, expression of amyloid precursor protein （App） and β -amyloid （A β ）, to investigate the mechanism of action of PNS in the treatment of AD in the senescence accelerated mouse-prone 8 （SAMP8） and compare the effects with huperzine A. DESIGN, TIME AND SETTING： A completely randomized grouping design, controlled animal experiment was performed in the Center for Research ＆ Development of New Drugs, Guangxi Traditional Chinese Medical University from July 2005 to April 2007. MATERIALS： Sixty male SAMP8 mice, aged 3 months, purchased from Tianjin Chinese Traditional Medical University of China, were divided into four groups： PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. PNS was provided by Weihe Pharmaceutical Co., Ltd. （batch No.： Z53021485, Yuxi, Yunan Province, China）. Huperzine A was provided by Zhenyuan Pharmaceutical Co., Ltd. （batch No.： 20040801, Zhejiang, China）. METHODS： The high-dosage group and low-dosage group were treated with 93.50 and 23.38 mg/kg PNS respectively per day and the huperzine A group was treated with 0.038 6 mg/kg huperzine A per day, all by intragastric administration, for 8 consecutive weeks. The same volume of double distilled water was given to the control group. MAIN OUTCOME MEASURES： After drug administration, learning and memory abilities were assessed by place navigation and spatial probe tests. The recording indices consisted of escape latency （time-to-platform）, and the percentage of swimming time spent in each quadrant. The number of A β 1-40, A β 1-42 and App immunopositive neurons in the brains of SAMP8 mice was analyzed by immunohistochemistry. The mRNA content ofApp, tau, acetylcholinesterase, and synaptophysin （Syp） was tested by real time PCR and RT-PCR. RESULTS： The PCR results show that PNS can downregulate the expression of the App gene and upregulate the expression of the Syp gene in the parietal cortex and hippocampus of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than those of the PNS low-dosage group and the huperzine A group （P 〈 0.05）. The results of the Morris water maze and immunohistochemistry indicated that PNS can improve the capacity for spatial learning and memory in SAMP8 mice, and reduce the content of A β 1-40, A β 1-42 and expression of App in the brains of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than that of the PNS low-dosage group and the huperzine A group （P 〈 0.05）. CONCLUSION： These results support the hypothesis that PNS plays a therapeutic and protective role on the pathological lesions and learning dysfunction of Alzheimer＇s disease. The therapeutic effects of PNS for Alzheimer＇s disease are possibly achieved through downregulating the expression of the App gene and upregulating the expression of the Syp gene. The therapeutic effects of PNS are dose-dependent and are greater than the effect of huperzine A.展开更多
Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD...Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.Methods:KLK levels in cerebrospinal fluid(CSF),as determined by ELISA,were compared between 32 AD patients stratified to A/T/(N)system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers.Associations between KLK levels and clinical severity,CSF and positron emission tomography(PET)based AD biomarkers were tested for.Results:Levels of KLK6 and KLK10 were significantly increased in AD.KLK6 differed significantly between AD A+/T+/N+and AD A+/T−/N+or NC with an AUC of 0.922.CSF pTau and tTau levels were significantly associated with KLK6 in AD.Conclusions:KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.展开更多
Alzheimer’s disease(AD)increasingly affects society due to aging populations.Even at pre-clinical stages,earlier and accurate diagnoses are essential for optimal AD management and improved clinical outcomes.Biomarker...Alzheimer’s disease(AD)increasingly affects society due to aging populations.Even at pre-clinical stages,earlier and accurate diagnoses are essential for optimal AD management and improved clinical outcomes.Biomarkers such as beta-amyloid(Aβ)or tau protein in cerebrospinal fluid(CSF)have been used as reliable markers to distinguish AD from non-AD,and predicting clinical outcomes,to attain these goals.However,given CSF access methods’invasiveness,these biomarkers are not used extensively in clinical settings.Blood Aβhas been proposed as an alternative biomarker since it is less invasive than CSF;however,sampling heterogeneity has limited its clinical applicability.In this review,we investigated blood Aβas a biomarker in AD and explored how Aβcan be facilitated as a viable biomarker for successful AD management.展开更多
基金financially supported by the National Natural Science Foundation of China,No.81573771the Natural Science Foundation of Jiangsu Province of China,No.BK20151599
文摘Mounting evidence indicates that amyloid β protein（Aβ） exerts neurotoxicity by disrupting the blood-brain barrier（BBB） in Alzheimer＇s disease. Hyperoside has neuroprotective effects both in vitro and in vivo against Aβ. Our previous study found that hyperoside suppressed Aβ1-42-induced leakage of the BBB, however, the mechanism remains unclear. In this study, bEnd.3 cells were pretreated with 50, 200, or 500 μM hyperoside for 2 hours, and then exposed to Aβ1-42 for 24 hours. Cell viability was determined using 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide assay. Flow cytometry and terminal deoxynucleotidyl transferase-mediated d UTP nick-end labeling assay were used to analyze cell apoptosis. Western blot assay was carried out to analyze expression levels of Bax, Bcl-2, cytochrome c, caspase-3, caspse-8, caspase-9, caspase-12, occludin, claudin-5, zonula occludens-1, matrix metalloproteinase-2（MMP-2）, and MMP-9. Exposure to Aβ1-42 alone remarkably induced bEnd.3 cell apoptosis; increased ratios of cleaved caspase-9/caspase-9, Bax/Bcl-2, cleav ed caspase-8/caspase-8, and cleaved caspase-12/caspase-12; increased expression of cytochrome c and activity of caspase-3; diminished levels of zonula occludens-1, claudin-5, and occludin; and increased levels of MMP-2 and MMP-9. However, hyperoside pretreatment reversed these changes in a dose-dependent manner. Our findings confirm that hyperoside alleviates fibrillar Aβ1-42-induced BBB disruption, thus offering a feasible therapeutic application in Alzheimer＇s disease.
文摘Crocetin is an aglycon of carotenoid extracted by saffron stigmas (Crocus sativus L.) and known to have a potent anti-oxidative effect. Amyliod β (Aβ), hallmark of Alzheimer’s disease, is reported to have neurotoxicity partly via oxidative stress. In this study, we investigated the effect of crocetin on hippocampal HT22 cell death induced by Aβ1-42. Furthermore, to clarify the mechanism underlying the protective effects of crocetin against Aβ1-42- induced cell death, we measured reactive oxygen species (ROS) production by CM-H2DCFDA kit assay. Crocetin at 1 -10 μM protected HT22 cells against Aβ1-42-induced neuronal cell death and decreased ROS production increased by Aβ1-42. These results that crocetin has the potent neuroprotective effect against Aβ1-42-induced cytotoxicity in hippocampal cells by attenuating oxidative stress, suggest that crocetin may provide a useful therapeutic strategy against Aβ-related disorders.
基金the National Natural Science Foundation of China, No: 30560189
文摘BACKGROUND： The pharmacological actions of Panax notoginseng saponins （PNS） lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheimer＇s disease. OBJECTIVE： Using the Morris water maze, immunohistochemistry, real-time PCR and RT-PCR, this study aimed to measure improvement in spatial learning, memory, expression of amyloid precursor protein （App） and β -amyloid （A β ）, to investigate the mechanism of action of PNS in the treatment of AD in the senescence accelerated mouse-prone 8 （SAMP8） and compare the effects with huperzine A. DESIGN, TIME AND SETTING： A completely randomized grouping design, controlled animal experiment was performed in the Center for Research ＆ Development of New Drugs, Guangxi Traditional Chinese Medical University from July 2005 to April 2007. MATERIALS： Sixty male SAMP8 mice, aged 3 months, purchased from Tianjin Chinese Traditional Medical University of China, were divided into four groups： PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. PNS was provided by Weihe Pharmaceutical Co., Ltd. （batch No.： Z53021485, Yuxi, Yunan Province, China）. Huperzine A was provided by Zhenyuan Pharmaceutical Co., Ltd. （batch No.： 20040801, Zhejiang, China）. METHODS： The high-dosage group and low-dosage group were treated with 93.50 and 23.38 mg/kg PNS respectively per day and the huperzine A group was treated with 0.038 6 mg/kg huperzine A per day, all by intragastric administration, for 8 consecutive weeks. The same volume of double distilled water was given to the control group. MAIN OUTCOME MEASURES： After drug administration, learning and memory abilities were assessed by place navigation and spatial probe tests. The recording indices consisted of escape latency （time-to-platform）, and the percentage of swimming time spent in each quadrant. The number of A β 1-40, A β 1-42 and App immunopositive neurons in the brains of SAMP8 mice was analyzed by immunohistochemistry. The mRNA content ofApp, tau, acetylcholinesterase, and synaptophysin （Syp） was tested by real time PCR and RT-PCR. RESULTS： The PCR results show that PNS can downregulate the expression of the App gene and upregulate the expression of the Syp gene in the parietal cortex and hippocampus of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than those of the PNS low-dosage group and the huperzine A group （P 〈 0.05）. The results of the Morris water maze and immunohistochemistry indicated that PNS can improve the capacity for spatial learning and memory in SAMP8 mice, and reduce the content of A β 1-40, A β 1-42 and expression of App in the brains of SAMP8 mice. The therapeutic effects of the PNS high-dosage group were greater than that of the PNS low-dosage group and the huperzine A group （P 〈 0.05）. CONCLUSION： These results support the hypothesis that PNS plays a therapeutic and protective role on the pathological lesions and learning dysfunction of Alzheimer＇s disease. The therapeutic effects of PNS for Alzheimer＇s disease are possibly achieved through downregulating the expression of the App gene and upregulating the expression of the Syp gene. The therapeutic effects of PNS are dose-dependent and are greater than the effect of huperzine A.
基金This work was supported by the German Research Foundation(DFG)and the Technical University of Munich(TUM)in the framework of the Open Access Publishing Program.
文摘Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.Methods:KLK levels in cerebrospinal fluid(CSF),as determined by ELISA,were compared between 32 AD patients stratified to A/T/(N)system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers.Associations between KLK levels and clinical severity,CSF and positron emission tomography(PET)based AD biomarkers were tested for.Results:Levels of KLK6 and KLK10 were significantly increased in AD.KLK6 differed significantly between AD A+/T+/N+and AD A+/T−/N+or NC with an AUC of 0.922.CSF pTau and tTau levels were significantly associated with KLK6 in AD.Conclusions:KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.
文摘Alzheimer’s disease(AD)increasingly affects society due to aging populations.Even at pre-clinical stages,earlier and accurate diagnoses are essential for optimal AD management and improved clinical outcomes.Biomarkers such as beta-amyloid(Aβ)or tau protein in cerebrospinal fluid(CSF)have been used as reliable markers to distinguish AD from non-AD,and predicting clinical outcomes,to attain these goals.However,given CSF access methods’invasiveness,these biomarkers are not used extensively in clinical settings.Blood Aβhas been proposed as an alternative biomarker since it is less invasive than CSF;however,sampling heterogeneity has limited its clinical applicability.In this review,we investigated blood Aβas a biomarker in AD and explored how Aβcan be facilitated as a viable biomarker for successful AD management.
