Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels.Immune inflammation is associated with the occurrence and development of MMD.However,the mechan...Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels.Immune inflammation is associated with the occurrence and development of MMD.However,the mechanisms underlying the formation of the abnormal vascular network remain unclear.Twenty-eight patients with MMD,26 ischemic stroke patients,and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor(GM-CSF)were higher in MMD patients than in healthy controls(P<0.01),and GM-CSF was mainly from Th1 and Th17 cells in MMD.We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis,inflammation,and chemotaxis.In summary,our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.展开更多
Chronic cerebral hypoperfusion leads to white matter injury(WMI),which subsequently causes neurodegeneration and even cognitive impairment.However,due to the lack of treatment specifically for WMI,novel recognized and...Chronic cerebral hypoperfusion leads to white matter injury(WMI),which subsequently causes neurodegeneration and even cognitive impairment.However,due to the lack of treatment specifically for WMI,novel recognized and effective therapeutic strategies are urgently needed.In this study,we found that honokiol and magnolol,two compounds derived from Magnolia officinalis,significantly facilitated the differentiation of primary oligodendrocyte precursor cells(OPCs)into mature oligodendrocytes,with a more prominent effect of the former compound.Moreover,our results demonstrated that honokiol treatment improved myelin injury,induced mature oligodendrocyte protein expression,attenuated cognitive decline,promoted oligodendrocyte regeneration,and inhibited astrocytic activation in the bilateral carotid artery stenosis model.Mechanistically,honokiol increased the phosphorylation of serine/threonine kinase(Akt)and mammalian target of rapamycin(mTOR)by activating cannabinoid receptor 1 during OPC differentiation.Collectively,our study indicates that honokiol might serve as a potential treatment for WMI in chronic cerebral ischemia.展开更多
Abnormal synchronous neuronal activity has been widely detected by brain imaging of autistic patients,but its underlying neural mechanism remains unclear.Compared with wild-type mice,our in vivo two-photon imaging sho...Abnormal synchronous neuronal activity has been widely detected by brain imaging of autistic patients,but its underlying neural mechanism remains unclear.Compared with wild-type mice,our in vivo two-photon imaging showed that transgenic(Tgl)mice over-expressing human autism risk gene MeCP2 exhibited higher neuronal synchrony in the young but lower synchrony in the adult stage.Whole-cell recording of neuronal pairs in brain slices revealed that higher neuronal synchrony in young postnatal Tgl mice was atributed mainly to more prevalent giant slow inward currents(SICs).Both in vivo and slice imaging further demonstrated more dynamic activity and higher synchrony in astrocytes from young Tgl mice.Blocking astrocytic gap junctions markedly decreased the generation of SICs and overall cell synchrony in the Tgl brain.Furthermore,the expression level of Cx43 protein and the coupling efficiency of astrocyte gap junctions remained unchanged in Tgi mice.Thus,astrocytic gap junctions facilitate but do not act as a direct trigger for the abnormal neuronal synchrony in young Tgl mice,revealing the potential role of the astrocyte network in the pathogenesis of MeCP2 duplication syndrome.展开更多
Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelin...Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter.However,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive dysfunction.We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests.In addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy.Meanwhile,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS.Moreover,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes.Interestingly,we found that MFG-E8 was mainly derived from astrocytes,not microglia.Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.展开更多
基金supported by the National Natural Science Foundation of China(82271334,82130036,81920108017,82171310)the National Science and Technology Innovation 2030--Major Program of"Brain Science and Brain-Like Research"(2022ZD0211800)+1 种基金Jiangsu Provincial‘333’High-level Talent Training Project Funding,the Key Research and Development Program of Jiangsu Province of China(BE2020620)Jiangsu Province Key Medical Discipline(ZDXK202216).
文摘Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal vessels.Immune inflammation is associated with the occurrence and development of MMD.However,the mechanisms underlying the formation of the abnormal vascular network remain unclear.Twenty-eight patients with MMD,26 ischemic stroke patients,and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor(GM-CSF)were higher in MMD patients than in healthy controls(P<0.01),and GM-CSF was mainly from Th1 and Th17 cells in MMD.We found that increased GM-CSF drove monocytes to secrete a series of cytokines associated with angiogenesis,inflammation,and chemotaxis.In summary,our findings demonstrate for the first time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.
基金This work was supported by the National Natural Science Foundation of China(81920108017 and 82130036)the Key Research and Development Program of Jiangsu Province of China(BE2020620)the Jiangsu Province Key Medical Discipline(ZDXKA2016020).
文摘Chronic cerebral hypoperfusion leads to white matter injury(WMI),which subsequently causes neurodegeneration and even cognitive impairment.However,due to the lack of treatment specifically for WMI,novel recognized and effective therapeutic strategies are urgently needed.In this study,we found that honokiol and magnolol,two compounds derived from Magnolia officinalis,significantly facilitated the differentiation of primary oligodendrocyte precursor cells(OPCs)into mature oligodendrocytes,with a more prominent effect of the former compound.Moreover,our results demonstrated that honokiol treatment improved myelin injury,induced mature oligodendrocyte protein expression,attenuated cognitive decline,promoted oligodendrocyte regeneration,and inhibited astrocytic activation in the bilateral carotid artery stenosis model.Mechanistically,honokiol increased the phosphorylation of serine/threonine kinase(Akt)and mammalian target of rapamycin(mTOR)by activating cannabinoid receptor 1 during OPC differentiation.Collectively,our study indicates that honokiol might serve as a potential treatment for WMI in chronic cerebral ischemia.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB32010100)a National Natural Science Foundation of China project(31671113)+1 种基金a Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)and the State Key Laboratory of Neuroscience.
文摘Abnormal synchronous neuronal activity has been widely detected by brain imaging of autistic patients,but its underlying neural mechanism remains unclear.Compared with wild-type mice,our in vivo two-photon imaging showed that transgenic(Tgl)mice over-expressing human autism risk gene MeCP2 exhibited higher neuronal synchrony in the young but lower synchrony in the adult stage.Whole-cell recording of neuronal pairs in brain slices revealed that higher neuronal synchrony in young postnatal Tgl mice was atributed mainly to more prevalent giant slow inward currents(SICs).Both in vivo and slice imaging further demonstrated more dynamic activity and higher synchrony in astrocytes from young Tgl mice.Blocking astrocytic gap junctions markedly decreased the generation of SICs and overall cell synchrony in the Tgl brain.Furthermore,the expression level of Cx43 protein and the coupling efficiency of astrocyte gap junctions remained unchanged in Tgi mice.Thus,astrocytic gap junctions facilitate but do not act as a direct trigger for the abnormal neuronal synchrony in young Tgl mice,revealing the potential role of the astrocyte network in the pathogenesis of MeCP2 duplication syndrome.
基金supported by the National Natural Science Foundation of China(81801147 and 81971112).
文摘Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter.However,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive dysfunction.We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests.In addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy.Meanwhile,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS.Moreover,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes.Interestingly,we found that MFG-E8 was mainly derived from astrocytes,not microglia.Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.