As a large group of cells in a central nervous system, astrocytes have a great influence on ion and energy metabolism in a nervous system. Disorders of neuronal ion and energy metabolism caused by impaired astrocytes ...As a large group of cells in a central nervous system, astrocytes have a great influence on ion and energy metabolism in a nervous system. Disorders of neuronal ion and energy metabolism caused by impaired astrocytes play a key role in the pathogenesis of epilepsy. This paper reviews the existing computational models of epileptogenesis resulting from impaired astrocytes and presents several open perspectives with regard to ion and energy metabolism-induced epileptogenesis in a neuron-astrocyte-capillary coupled model.展开更多
Background: Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considere...Background: Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating neurons.Methods: We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-q PCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced neurons.Results: The results showed that human astrocytes could be rapidly and efficiently converted into motor neuronlike cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, MAP2, Neu N, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VACh T. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant astrocytes.Conclusions: The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine.展开更多
Experimental records in the cerebral cortex indicate that ammonia injection can lead to seizures. Considering that astrocytes play a vital role in mediating the uptake and absorption of ammonium ions in the extracellu...Experimental records in the cerebral cortex indicate that ammonia injection can lead to seizures. Considering that astrocytes play a vital role in mediating the uptake and absorption of ammonium ions in the extracellular space of the cortical circuit, we constructed a new astrocyte neuron coupling model, which is composed of a neuron and its astrocytes connected through the extracellular space, taking into account of the influence of extracellular ammonium ions. The numerical results verified the previous experimental observation that obtained epileptic firing modes of neurons and postsynaptic GABA reversal potential depolarization triggered by ammonia injection. In addition, we also determined the concentration–response relationship between the ammonium ion concentration and the time of entering epilepsy and predicted the threshold of the ammonium ion concentration for the onset of epilepsy.展开更多
Extremely low-frequency magnetic field is widely used as a noninvasive stimulation method in clinical practice and basic research. Electrical field induced from magnetic pulse can decrease or increase neuronal electri...Extremely low-frequency magnetic field is widely used as a noninvasive stimulation method in clinical practice and basic research. Electrical field induced from magnetic pulse can decrease or increase neuronal electrical activity. However, the cellular mechanism underlying the effects of magnetic field is not clear from experimental data. Recent studies have demonstrated that "non-neuronal" cells, especially astrocytes, may be the potential effector for transcranial magnetic stimulation(TMS). In the present study, we implemented a neural–astrocyte microcircuit computational model based on hippocampal architecture to investigate the biological effects of different magnetic field frequencies on cells. The purpose of the present study is to elucidate the main influencing factors of MS to allow a better understanding of its mechanisms.Our model reproduced the basic characteristics of the neuron and astrocyte response to different magnetic stimulation. The results predict that interneurons with lower firing thresholds were more active in magnetic fields by contrast to pyramidal neurons. And the synaptic coupling strength between the connected neurons may be one of the critical factor to affect the effect of magnetic field on cells. In addition, the simulations show that astrocytes can decrease or increase slow inward currents(SICs) to finely tune neuronal excitation, which suggests their key role in excitatory–inhibitory balance. The interaction between neurons and astrocytes may represent a novel target for effective therapeutic strategies involving magnetic stimulation.展开更多
objective: Two groups of rats were microinjected with kainic acid (KA) and irradiated with gam ma knife respectively on unilateral nucleus caudate-putamen to compare the response of astrocytes. Methods: The astrocytes...objective: Two groups of rats were microinjected with kainic acid (KA) and irradiated with gam ma knife respectively on unilateral nucleus caudate-putamen to compare the response of astrocytes. Methods: The astrocytes were identified with anti-GFAP immunohistochemical ABC method and the progress of their reaction to the 2 insults was examined from 3 h to 30 d after the lesion. Results: Both lesions could induce hyperplasia and hypertrophy of astrocytes and 2 types of GFAP-ir cells were found, one with small cell body and thin process, and the other with hypertrophic cell body and thick and long process. The timecourse of GFAP expression in the 2 groups was different. In KA microinjection group, large necrotic area was ob served in the target within 24 h. Three days later, a few astrocytes appeared around the necrosis. With in crease of the survival time, hyperplasia and hypertrophy of astrocytes began to increase. Whereas in gamma knife group, hyperplasia and hypertrophy were evident from 3 h to 7 d and necrotic dots could be seen in the target on day 14. On day 30, necrosis was tnore obvious with gradual variations in GFAP expression around the necrotic area. Conclusion: The above results indicated that GFAP could be used as a marker for CNS in jury; the difference in their timing and distribution pattern suggested different mechanisms in KA microinjec tion group and gamma-knife irradiation group.展开更多
Astrocytes have a regulatory function on the central nervous system(CNS), especially in the temperature-sensitive hippocampal region. In order to explore the thermosensitive dynamic mechanism of astrocytes in the CNS,...Astrocytes have a regulatory function on the central nervous system(CNS), especially in the temperature-sensitive hippocampal region. In order to explore the thermosensitive dynamic mechanism of astrocytes in the CNS, we establish a neuron-astrocyte minimum system to analyze the synchronization change characteristics based on the Hodgkin-Huxley model, in which a pyramidal cell and an interneuron are connected by an astrocyte. The temperature range is set as 0-40 ℃ to juggle between theoretical calculation and the reality of a brain environment. It is shown that the synchronization of thermosensitive neurons exhibits nonlinear behavior with changes in astrocyte parameters. At a temperature range of0 ℃-18 ℃, the effects of the astrocyte can provide a tremendous influence on neurons in synchronization. We find the existence of a value for inositol triphosphate(IP_(3)) production rate and feedback intensities of astrocytes to neurons, which can ensure the weak synchronization of two neurons. In addition, it is revealed that the regulation of astrocytes to pyramidal cells is more sensitive than that to interneurons. Finally, it is shown that the synchronization and phase transition of neurons depend on the change in Ca^(2+) concentration at the temperature of weak synchronization. The results in this paper provide some enlightenment on the mechanism of cognitive dysfunction and neurological disorders with astrocytes.展开更多
Glial cell line-derived neurotrophic factor(GDNF)is highly expressed in glioblastomas and a potent migration-promoting factor.However,its underlying mechanisms have not yet been clearly elucidated.In this work,we foun...Glial cell line-derived neurotrophic factor(GDNF)is highly expressed in glioblastomas and a potent migration-promoting factor.However,its underlying mechanisms have not yet been clearly elucidated.In this work,we found astrocytes treated by GDNF significantly promoted the migration of glioblastoma cells.RNA-seq data suggested that Lipocalin 2(Lcn2)was increased in astrocytes after GDNF treatment.F urther investigation confirmed that GDNF enhanced the expression and secretion of Lcn2 in astrocytes.Co-culture experiments revealed that Lcn2 knockdown in astrocytes strongly inhibited GDNF-induced glioblastoma cell migration,Mechanically,the binding between Len2 and MMP9 was increased by GDNF using co-immunoprecipitation,and Lcn2 knockdown reduced the combination of Lcn2 and MMP9.Moreover,the effect of GDNF on glioblastoma cell migra tion was inhibited when blocking the combination of Lcn2 and MMP9.In conclusion,the present study indicated that GDNF boosted the secretion of Lcn2 from astrocytes,further attributing to glioma cell migration via upregulating the combination of Lcn2 and MMP9.Therefore,GDNF may be a novel therapeutic target for the treatment of glioblastoma.23.miR-200a suppresses glioma cell migration and invasion via directly targeting MAGED4.Zhang Qingmei,Wu Huixian,Liu Chang,Luo Xin,Zhao Wenjing,Ge Yingying,Chen Fang,Nong Weixia,Xiao Shaowen,Xie Xioxun,Luo Bin.展开更多
Reactive astrocytes are a double edged sword for traumatic brain injury(TBD),whether their overall effect on injury is beneficial or harmful depends on the balance between the loss and gain of function.However,the mec...Reactive astrocytes are a double edged sword for traumatic brain injury(TBD),whether their overall effect on injury is beneficial or harmful depends on the balance between the loss and gain of function.However,the mechanism of reactive astrocytes after TBI is poorly understood.Recently more and more studies have been conducted to regulate the gene expression of astrocytes as a target to treat the disease.Here,we generated early postnatal TBI in the mouse cortex,indicating typical reactive astrocytes and glial scar were observed around damaged area;We next deleted Sox2 in astrocytes to observe its effects on reactive astrocytes and tissue repair after postnatal injury in the mouse cortex.As a result,specific deletion of Sox2 in astrocytes greatly inhibited the formation of reactive astrocytes and glial scars,and significantly promoted nerve regeneration in the damaged area and post injured repair.Together,our study indicate that Sox2 plays an important role in reactive astrocytes after early postnatal TBI in the mouse cortex.Therefore,Sox2 in astrocytes may be a putative target to develop new therapeutic tools for TBI treatment.展开更多
Acute inflammation is a central component in the progression of spinal cord injury(SCI).Anti-inflammatory drugs used in the clinic are often administered systemically at high doses,which can paradoxically increase inf...Acute inflammation is a central component in the progression of spinal cord injury(SCI).Anti-inflammatory drugs used in the clinic are often administered systemically at high doses,which can paradoxically increase inflammation and result in drug toxicity.A cluster-like mesoporous silica/arctigenin/CAQK composite(MSN-FC@ARCG)drug delivery system was designed to avoid systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord.In this nanosystem,mesoporous silica was modified with the FITC fluorescent molecule and CAQK peptides that target brain injury and SCI sites.The size of the nanocarrier was kept at approximately 100 nm to enable penetration of the blood–brain barrier.Arctigenin,a Chinese herbal medicine,was loaded into the nanosystem to reduce inflammation.The in vivo results showed that MSN-FC@ARC-G could attenuate inflammation at the injury site.Behavior and morphology experiments suggested that MSN-FC@ARC-G could diminish local microenvironment damage,especially reducing the expression of interleukin-17(IL-17) and IL-17-related inflammatory factors,inhibiting the activation of astrocytes,thus protecting neurons and accelerating the recovery of SCI.Our study demonstrated that this novel,silica-based drug delivery system has promising potential for clinical application in SCI therapy.展开更多
Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mous...Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of mice.After the mice were sacrificed,the hippocampus was excised for further analysis.Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte.Western blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory cytokines.Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus.Absence of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD.However,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.展开更多
基金Project supported by the National Natural Science Foundation of China(Grant No.11772242)。
文摘As a large group of cells in a central nervous system, astrocytes have a great influence on ion and energy metabolism in a nervous system. Disorders of neuronal ion and energy metabolism caused by impaired astrocytes play a key role in the pathogenesis of epilepsy. This paper reviews the existing computational models of epileptogenesis resulting from impaired astrocytes and presents several open perspectives with regard to ion and energy metabolism-induced epileptogenesis in a neuron-astrocyte-capillary coupled model.
基金supported in part by the National Nature Science Foundation of China (81830064, 81721092)the National Key Research and Development Plan (2017YFC1103304)+1 种基金the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-059)the Military Medical Research and Development Projects (AWS17J005, 2019–126)。
文摘Background: Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating neurons.Methods: We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-q PCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced neurons.Results: The results showed that human astrocytes could be rapidly and efficiently converted into motor neuronlike cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, MAP2, Neu N, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VACh T. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant astrocytes.Conclusions: The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine.
基金supported by the National Natural Science Foundation of China (Grant Nos. 12132012 and 11972275)the National Science Foundation for Young Scientists of China (Grant No. 12102240)。
文摘Experimental records in the cerebral cortex indicate that ammonia injection can lead to seizures. Considering that astrocytes play a vital role in mediating the uptake and absorption of ammonium ions in the extracellular space of the cortical circuit, we constructed a new astrocyte neuron coupling model, which is composed of a neuron and its astrocytes connected through the extracellular space, taking into account of the influence of extracellular ammonium ions. The numerical results verified the previous experimental observation that obtained epileptic firing modes of neurons and postsynaptic GABA reversal potential depolarization triggered by ammonia injection. In addition, we also determined the concentration–response relationship between the ammonium ion concentration and the time of entering epilepsy and predicted the threshold of the ammonium ion concentration for the onset of epilepsy.
基金supported by the National Natural Science Foundation of China (Grant No. 61673158)the Youth Talent Support Program of Hebei Province,China(Grant No. BJ2019044)。
文摘Extremely low-frequency magnetic field is widely used as a noninvasive stimulation method in clinical practice and basic research. Electrical field induced from magnetic pulse can decrease or increase neuronal electrical activity. However, the cellular mechanism underlying the effects of magnetic field is not clear from experimental data. Recent studies have demonstrated that "non-neuronal" cells, especially astrocytes, may be the potential effector for transcranial magnetic stimulation(TMS). In the present study, we implemented a neural–astrocyte microcircuit computational model based on hippocampal architecture to investigate the biological effects of different magnetic field frequencies on cells. The purpose of the present study is to elucidate the main influencing factors of MS to allow a better understanding of its mechanisms.Our model reproduced the basic characteristics of the neuron and astrocyte response to different magnetic stimulation. The results predict that interneurons with lower firing thresholds were more active in magnetic fields by contrast to pyramidal neurons. And the synaptic coupling strength between the connected neurons may be one of the critical factor to affect the effect of magnetic field on cells. In addition, the simulations show that astrocytes can decrease or increase slow inward currents(SICs) to finely tune neuronal excitation, which suggests their key role in excitatory–inhibitory balance. The interaction between neurons and astrocytes may represent a novel target for effective therapeutic strategies involving magnetic stimulation.
文摘objective: Two groups of rats were microinjected with kainic acid (KA) and irradiated with gam ma knife respectively on unilateral nucleus caudate-putamen to compare the response of astrocytes. Methods: The astrocytes were identified with anti-GFAP immunohistochemical ABC method and the progress of their reaction to the 2 insults was examined from 3 h to 30 d after the lesion. Results: Both lesions could induce hyperplasia and hypertrophy of astrocytes and 2 types of GFAP-ir cells were found, one with small cell body and thin process, and the other with hypertrophic cell body and thick and long process. The timecourse of GFAP expression in the 2 groups was different. In KA microinjection group, large necrotic area was ob served in the target within 24 h. Three days later, a few astrocytes appeared around the necrosis. With in crease of the survival time, hyperplasia and hypertrophy of astrocytes began to increase. Whereas in gamma knife group, hyperplasia and hypertrophy were evident from 3 h to 7 d and necrotic dots could be seen in the target on day 14. On day 30, necrosis was tnore obvious with gradual variations in GFAP expression around the necrotic area. Conclusion: The above results indicated that GFAP could be used as a marker for CNS in jury; the difference in their timing and distribution pattern suggested different mechanisms in KA microinjec tion group and gamma-knife irradiation group.
基金Project supported by the National Natural Science Foundation of China (Grant Nos. 51607056, 51737003, and 51877069)State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology (Grant No. EERI PI2020006)。
文摘Astrocytes have a regulatory function on the central nervous system(CNS), especially in the temperature-sensitive hippocampal region. In order to explore the thermosensitive dynamic mechanism of astrocytes in the CNS, we establish a neuron-astrocyte minimum system to analyze the synchronization change characteristics based on the Hodgkin-Huxley model, in which a pyramidal cell and an interneuron are connected by an astrocyte. The temperature range is set as 0-40 ℃ to juggle between theoretical calculation and the reality of a brain environment. It is shown that the synchronization of thermosensitive neurons exhibits nonlinear behavior with changes in astrocyte parameters. At a temperature range of0 ℃-18 ℃, the effects of the astrocyte can provide a tremendous influence on neurons in synchronization. We find the existence of a value for inositol triphosphate(IP_(3)) production rate and feedback intensities of astrocytes to neurons, which can ensure the weak synchronization of two neurons. In addition, it is revealed that the regulation of astrocytes to pyramidal cells is more sensitive than that to interneurons. Finally, it is shown that the synchronization and phase transition of neurons depend on the change in Ca^(2+) concentration at the temperature of weak synchronization. The results in this paper provide some enlightenment on the mechanism of cognitive dysfunction and neurological disorders with astrocytes.
文摘Glial cell line-derived neurotrophic factor(GDNF)is highly expressed in glioblastomas and a potent migration-promoting factor.However,its underlying mechanisms have not yet been clearly elucidated.In this work,we found astrocytes treated by GDNF significantly promoted the migration of glioblastoma cells.RNA-seq data suggested that Lipocalin 2(Lcn2)was increased in astrocytes after GDNF treatment.F urther investigation confirmed that GDNF enhanced the expression and secretion of Lcn2 in astrocytes.Co-culture experiments revealed that Lcn2 knockdown in astrocytes strongly inhibited GDNF-induced glioblastoma cell migration,Mechanically,the binding between Len2 and MMP9 was increased by GDNF using co-immunoprecipitation,and Lcn2 knockdown reduced the combination of Lcn2 and MMP9.Moreover,the effect of GDNF on glioblastoma cell migra tion was inhibited when blocking the combination of Lcn2 and MMP9.In conclusion,the present study indicated that GDNF boosted the secretion of Lcn2 from astrocytes,further attributing to glioma cell migration via upregulating the combination of Lcn2 and MMP9.Therefore,GDNF may be a novel therapeutic target for the treatment of glioblastoma.23.miR-200a suppresses glioma cell migration and invasion via directly targeting MAGED4.Zhang Qingmei,Wu Huixian,Liu Chang,Luo Xin,Zhao Wenjing,Ge Yingying,Chen Fang,Nong Weixia,Xiao Shaowen,Xie Xioxun,Luo Bin.
文摘Reactive astrocytes are a double edged sword for traumatic brain injury(TBD),whether their overall effect on injury is beneficial or harmful depends on the balance between the loss and gain of function.However,the mechanism of reactive astrocytes after TBI is poorly understood.Recently more and more studies have been conducted to regulate the gene expression of astrocytes as a target to treat the disease.Here,we generated early postnatal TBI in the mouse cortex,indicating typical reactive astrocytes and glial scar were observed around damaged area;We next deleted Sox2 in astrocytes to observe its effects on reactive astrocytes and tissue repair after postnatal injury in the mouse cortex.As a result,specific deletion of Sox2 in astrocytes greatly inhibited the formation of reactive astrocytes and glial scars,and significantly promoted nerve regeneration in the damaged area and post injured repair.Together,our study indicate that Sox2 plays an important role in reactive astrocytes after early postnatal TBI in the mouse cortex.Therefore,Sox2 in astrocytes may be a putative target to develop new therapeutic tools for TBI treatment.
基金supported by the National Natural Science Foundation of China(Nos.31670969,51302089,and 31571030)the Fundamental Research Funds for the Central Universities(No.21617428)+3 种基金Key Program of Traditional Chinese Medicine of Guangdong Province(No.20173018)The Science and Technology Program of Jiangmen City of China(No.2017A2004)Natural Science Foundation of Guangdong Province(No.2018A030313576)Science and Technology Program of Guangzhou(No.201803010001)
文摘Acute inflammation is a central component in the progression of spinal cord injury(SCI).Anti-inflammatory drugs used in the clinic are often administered systemically at high doses,which can paradoxically increase inflammation and result in drug toxicity.A cluster-like mesoporous silica/arctigenin/CAQK composite(MSN-FC@ARCG)drug delivery system was designed to avoid systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord.In this nanosystem,mesoporous silica was modified with the FITC fluorescent molecule and CAQK peptides that target brain injury and SCI sites.The size of the nanocarrier was kept at approximately 100 nm to enable penetration of the blood–brain barrier.Arctigenin,a Chinese herbal medicine,was loaded into the nanosystem to reduce inflammation.The in vivo results showed that MSN-FC@ARC-G could attenuate inflammation at the injury site.Behavior and morphology experiments suggested that MSN-FC@ARC-G could diminish local microenvironment damage,especially reducing the expression of interleukin-17(IL-17) and IL-17-related inflammatory factors,inhibiting the activation of astrocytes,thus protecting neurons and accelerating the recovery of SCI.Our study demonstrated that this novel,silica-based drug delivery system has promising potential for clinical application in SCI therapy.
基金This study was partly supported by the National Natural Science Foundation of China(81771360).
文摘Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of mice.After the mice were sacrificed,the hippocampus was excised for further analysis.Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte.Western blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory cytokines.Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus.Absence of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD.However,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.
