Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchyma...Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.展开更多
目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免...目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免疫印迹法检测各组细胞CB2受体和酪氨酸羟化酶(TH)蛋白的表达,用流式细胞仪检测细胞线粒体膜电位(ΔΨm)的变化。结果 与C组相比,M组的CB2受体蛋白表达下降( P <0.01);经JWH-133预处理后,CB2受体蛋白表达高于M组( P <0.01),此作用可被AM630所阻断;与C组相比,M组的TH表达降低( P <0.05),经JWH-133预处理后,TH表达高于M组( P <0.05),AM630预处理可抑制此作用;与C组相比,M组细胞的ΔΨm明显下降( P <0.01),经JWH-133预处理后,细胞ΔΨm下降幅度变小( P <0.01),此作用可被AM630所阻断。结论 CB2受体激活可以抑制MPP +对SH-SY5Y细胞的损伤作用。展开更多
基金supported by the National Key Research and Development Program (grant no. 2021YFA1101301)the National Natural Science Foundation of China (grant no. 82225027, 82271419, 81820108013, 62127810, 81901902)+1 种基金Shanghai Rising-Star Program (grant no. 22QA1408200)the Fundamental Research Funds for the Central Universities(no. 22120220555, no. 22120230292, no. 22120230138)
文摘Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.
文摘目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免疫印迹法检测各组细胞CB2受体和酪氨酸羟化酶(TH)蛋白的表达,用流式细胞仪检测细胞线粒体膜电位(ΔΨm)的变化。结果 与C组相比,M组的CB2受体蛋白表达下降( P <0.01);经JWH-133预处理后,CB2受体蛋白表达高于M组( P <0.01),此作用可被AM630所阻断;与C组相比,M组的TH表达降低( P <0.05),经JWH-133预处理后,TH表达高于M组( P <0.05),AM630预处理可抑制此作用;与C组相比,M组细胞的ΔΨm明显下降( P <0.01),经JWH-133预处理后,细胞ΔΨm下降幅度变小( P <0.01),此作用可被AM630所阻断。结论 CB2受体激活可以抑制MPP +对SH-SY5Y细胞的损伤作用。
基金supported by the National Natural Science Foundation of China(NSFC30973637)Qianjiang talents project of technology office in Zhejiang province(2010R10048)
