Synaptic abnormalities are a cardinal feature of Alzheimer’s disease(AD)that are known to arise as the disease progresses.A growing body of evidence suggests that pathological alterations to neuronal circuits and syn...Synaptic abnormalities are a cardinal feature of Alzheimer’s disease(AD)that are known to arise as the disease progresses.A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloidβ(Aβ)and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD.Brain-derived neurotrophic factors(BDNFs)play an important role in maintaining synaptic plasticity in learning and memory.Considering AD as a synaptic disorder,BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD.Although depletion of BDNF has been linked with Aβaccumulation,tau phosphorylation,neuroinflammation and neuronal apoptosis,the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown.Here,we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling.We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.展开更多
BACKGROUND Post-stroke cognitive impairment(PSCI)is not only a common consequence of stroke but also an important factor for adverse prognosis of patients.Biochemical indicators such as blood lipids and blood pressure...BACKGROUND Post-stroke cognitive impairment(PSCI)is not only a common consequence of stroke but also an important factor for adverse prognosis of patients.Biochemical indicators such as blood lipids and blood pressure are affected by many factors,and the ability of evaluating the progress of patients with PSCI is insufficient.Therefore,it is necessary to find sensitive markers for predicting the progress of patients and avoiding PSCI.Recent studies have shown thatβ-amyloid protein 1-42(Aβ1-42)and thyroid hormone levels are closely related to PSCI,which may be the influencing factors of PSCI,but there are few related studies.AIM To investigate the relationship between serum levels of Aβand thyroid hormones in acute stage and PSCI and its predicted value.METHODS A total of 195 patients with acute cerebral infarction confirmed from June 2016 to January 2018 were enrolled in this study.Baseline data and serological indicators were recorded to assess cognitive function of patients.All patients were followed up for 1 year.Their cognitive functions were evaluated within 1 wk,3 mo,6 mo and 1 yr after stroke.At the end of follow-up,the patients were divided into PSCI and non-PSCI according to Montreal cognitive assessment score,and the relationship between biochemical indexes and the progression of PSCI was explored.RESULTS Compared with patients with non-PSCI,the levels of Aβ1-42,triiodothyronine(T3)and free thyroxin were lower in the patients with PSCI.Repeated measures analysis of variance showed that the overall content of Aβ1-42 and T3 in PSCI was also lower than that of the non-PSCI patients.Further analysis revealed that Aβ1-42(r=0.348),T3(r=0.273)and free thyroxin(r=0.214)were positively correlated with disease progression(P<0.05),suggesting that these indicators have the potential to predict disease progression and outcome.Cox regression analysis showed that Aβ1-42 and T3 were important factors of PSCI.Then stratified analysis showed that the lower the Aβ1-42 and T3,the higher risk of PSCI in patients who展开更多
Objective To investigate the neuroprotective action of astragaloside Ⅳ(AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42(Aβ1-42) in rats and elucidate its underlying molecular mechanisms....Objective To investigate the neuroprotective action of astragaloside Ⅳ(AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42(Aβ1-42) in rats and elucidate its underlying molecular mechanisms.Methods Adult-male Sprague-Dawley rats(230-250 g) were divided into six groups randomly: control, Aβ1-42, AS-Ⅳ, Aβ1-42 plus 5 mg/kg·d AS-Ⅳ, Aβ1-42 plus 25 mg/kg·d AS-Ⅳ, and Aβ1-42 plus 50 mg/kg·d AS-Ⅳ groups. Aβ1-42 were delivered by intracerebroventricular injection under the guidance of a brain stereotaxic apparatus. The Morris water maze test(hidden platform test, probe trials, visible platform test) was performed one week after Aβ1-42 injection to obtain the ability of rat spatial learning and memory. AS-Ⅳ(5, 25 and 50 mg/kg·d) was administrated intraperitoneally once per day from the 8 th day after Aβ1-42 injection for 5 consecutive days. Average escape latencies, distances for searching for the platform under water and the percentage of total time elapsed and distance swam in the right quadrant after removing platform were determined by behavior softwaresystem. The vision and swim speeds of rats were also determined to exclude the effect of these factors on the parameters of learning and memory. After behavioral tests, the rats were sacrificed immediately by decapitation. Hippocampus were collected. The enzyme activities of superoxide dismutase(SOD), glutathione peroxidase(GSH-px) and catalase(CAT) in the hippocampus obtained from different-treated rat brain were measured by following the manufacturer’s instructions. The levels of interleukin-1 beta(IL-1β) and tumor necrosis factor-alpha(TNF-α) in tissue lysates were assayed with ELISA.Results The water maze test results indicated that chronic treatments with AS-Ⅳ effectively protected the rats from Aβ1-42-induced spatial learning and memory impairment. Furthermore, the activities of SOD, GSH-px and CAT decreased by Aβ1-42 were also restored by AS-Ⅳ treatment in the hippocampus of rats. In addition, AS-Ⅳ signi展开更多
目的研究五味子乙素抑制M146L细胞A4β2生成的机制。方法体外培养高效表达Aβ42的M146L细胞株,分别加入不同浓度的五味子乙素(1.67,5.00和15.00μg.mL-1)、β分泌酶抑制剂(S4562,100.00μg.mL-1)和γ分泌酶抑制剂(S2188,13.68μg.mL-1)...目的研究五味子乙素抑制M146L细胞A4β2生成的机制。方法体外培养高效表达Aβ42的M146L细胞株,分别加入不同浓度的五味子乙素(1.67,5.00和15.00μg.mL-1)、β分泌酶抑制剂(S4562,100.00μg.mL-1)和γ分泌酶抑制剂(S2188,13.68μg.mL-1)。用CCK-8(cell counting k it-8)比色法检测不同处理对M146L细胞活性的影响;用ELISA法测定M146L细胞所分泌的Aβ42的变化;用W estern b lotting检测APP的β分泌酶剪切产物C99蛋白的含量变化,结合用β和γ分泌酶活性试剂盒,检测五味子乙素对这两种酶活性的影响。结果不同处理因素对M146L细胞的存活率均无影响,不具有细胞毒作用。中、高剂量的五味子乙素均不同程度地抑制M146L细胞分泌A4β2及γ分泌酶的活性,但都不改变M146L细胞C99蛋白的含量及β分泌酶的活性。结论五味子乙素可抑制γ分泌酶活性,其降低A4β2生成是通过抑制γ分泌酶的活性来实现的。展开更多
基金National Natural Science Foundation of China(81903824)(L.G.).
文摘Synaptic abnormalities are a cardinal feature of Alzheimer’s disease(AD)that are known to arise as the disease progresses.A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloidβ(Aβ)and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD.Brain-derived neurotrophic factors(BDNFs)play an important role in maintaining synaptic plasticity in learning and memory.Considering AD as a synaptic disorder,BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD.Although depletion of BDNF has been linked with Aβaccumulation,tau phosphorylation,neuroinflammation and neuronal apoptosis,the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown.Here,we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling.We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.
基金supported by the Special Foundation for High Schools Doctoral Program, Ministry of Education, China (No. 20101417110001)the Scientific Research Foundation for the Returned Overseas Chinese Scholars in Shanxi Province, China (No. 2010-51)the Natural Science Foundation of Shanxi Province, China (No. 2010011049-3)
基金Supported by Science and Technology Support Projects in Biomedicine Field of Shanghai Science and Technology Commission,No.19441907500Naval Medical University Military Medical Innovation,No.2017JS07Science and Technology Action Innovation Program by Science and Technology Commission of Shanghai,No.17411950104
文摘BACKGROUND Post-stroke cognitive impairment(PSCI)is not only a common consequence of stroke but also an important factor for adverse prognosis of patients.Biochemical indicators such as blood lipids and blood pressure are affected by many factors,and the ability of evaluating the progress of patients with PSCI is insufficient.Therefore,it is necessary to find sensitive markers for predicting the progress of patients and avoiding PSCI.Recent studies have shown thatβ-amyloid protein 1-42(Aβ1-42)and thyroid hormone levels are closely related to PSCI,which may be the influencing factors of PSCI,but there are few related studies.AIM To investigate the relationship between serum levels of Aβand thyroid hormones in acute stage and PSCI and its predicted value.METHODS A total of 195 patients with acute cerebral infarction confirmed from June 2016 to January 2018 were enrolled in this study.Baseline data and serological indicators were recorded to assess cognitive function of patients.All patients were followed up for 1 year.Their cognitive functions were evaluated within 1 wk,3 mo,6 mo and 1 yr after stroke.At the end of follow-up,the patients were divided into PSCI and non-PSCI according to Montreal cognitive assessment score,and the relationship between biochemical indexes and the progression of PSCI was explored.RESULTS Compared with patients with non-PSCI,the levels of Aβ1-42,triiodothyronine(T3)and free thyroxin were lower in the patients with PSCI.Repeated measures analysis of variance showed that the overall content of Aβ1-42 and T3 in PSCI was also lower than that of the non-PSCI patients.Further analysis revealed that Aβ1-42(r=0.348),T3(r=0.273)and free thyroxin(r=0.214)were positively correlated with disease progression(P<0.05),suggesting that these indicators have the potential to predict disease progression and outcome.Cox regression analysis showed that Aβ1-42 and T3 were important factors of PSCI.Then stratified analysis showed that the lower the Aβ1-42 and T3,the higher risk of PSCI in patients who
基金Supported by the Natural Science Foundation of Shaanxi Province of China(2015JQ8299)National Science Foundation of China(81703842)Traditional Chinese Medicine Scientific Research Projects of Shaanxi Province of China(JCMS032)
文摘Objective To investigate the neuroprotective action of astragaloside Ⅳ(AS-Ⅳ) on spatial learning and memory impairment induced by amyloid-beta 1-42(Aβ1-42) in rats and elucidate its underlying molecular mechanisms.Methods Adult-male Sprague-Dawley rats(230-250 g) were divided into six groups randomly: control, Aβ1-42, AS-Ⅳ, Aβ1-42 plus 5 mg/kg·d AS-Ⅳ, Aβ1-42 plus 25 mg/kg·d AS-Ⅳ, and Aβ1-42 plus 50 mg/kg·d AS-Ⅳ groups. Aβ1-42 were delivered by intracerebroventricular injection under the guidance of a brain stereotaxic apparatus. The Morris water maze test(hidden platform test, probe trials, visible platform test) was performed one week after Aβ1-42 injection to obtain the ability of rat spatial learning and memory. AS-Ⅳ(5, 25 and 50 mg/kg·d) was administrated intraperitoneally once per day from the 8 th day after Aβ1-42 injection for 5 consecutive days. Average escape latencies, distances for searching for the platform under water and the percentage of total time elapsed and distance swam in the right quadrant after removing platform were determined by behavior softwaresystem. The vision and swim speeds of rats were also determined to exclude the effect of these factors on the parameters of learning and memory. After behavioral tests, the rats were sacrificed immediately by decapitation. Hippocampus were collected. The enzyme activities of superoxide dismutase(SOD), glutathione peroxidase(GSH-px) and catalase(CAT) in the hippocampus obtained from different-treated rat brain were measured by following the manufacturer’s instructions. The levels of interleukin-1 beta(IL-1β) and tumor necrosis factor-alpha(TNF-α) in tissue lysates were assayed with ELISA.Results The water maze test results indicated that chronic treatments with AS-Ⅳ effectively protected the rats from Aβ1-42-induced spatial learning and memory impairment. Furthermore, the activities of SOD, GSH-px and CAT decreased by Aβ1-42 were also restored by AS-Ⅳ treatment in the hippocampus of rats. In addition, AS-Ⅳ signi
文摘目的研究五味子乙素抑制M146L细胞A4β2生成的机制。方法体外培养高效表达Aβ42的M146L细胞株,分别加入不同浓度的五味子乙素(1.67,5.00和15.00μg.mL-1)、β分泌酶抑制剂(S4562,100.00μg.mL-1)和γ分泌酶抑制剂(S2188,13.68μg.mL-1)。用CCK-8(cell counting k it-8)比色法检测不同处理对M146L细胞活性的影响;用ELISA法测定M146L细胞所分泌的Aβ42的变化;用W estern b lotting检测APP的β分泌酶剪切产物C99蛋白的含量变化,结合用β和γ分泌酶活性试剂盒,检测五味子乙素对这两种酶活性的影响。结果不同处理因素对M146L细胞的存活率均无影响,不具有细胞毒作用。中、高剂量的五味子乙素均不同程度地抑制M146L细胞分泌A4β2及γ分泌酶的活性,但都不改变M146L细胞C99蛋白的含量及β分泌酶的活性。结论五味子乙素可抑制γ分泌酶活性,其降低A4β2生成是通过抑制γ分泌酶的活性来实现的。
