Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phen...Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.展开更多
Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, and sustaining neuroprotective effects. ...Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, and sustaining neuroprotective effects. Astrocytes become activated as a result of inflammatory responses during the progression of pathological changes associated with neurodegenerative disorders. Reactive astrocytes(neurotoxic A1 and neuroprotective A2) are triggered during disease progression and pathogenesis due to neuroinflammation and ischemia. However, only a limited body of literature describes morphological and functional changes of astrocytes during the progression of neurodegenerative diseases. The present review investigated the detrimental and beneficial roles of astrocytes in neurodegenerative diseases reported in recent studies, as these cells have promising therapeutic potential and offer new approaches for treatment of neurodegenerative diseases.展开更多
Ras homolog(Rho)-associated kinases(ROCKs)belong to the serine-threonine kinase family,which plays a pivotal role in regulating the damage,survival,axon guidance,and regeneration of neurons.ROCKs are also involved in ...Ras homolog(Rho)-associated kinases(ROCKs)belong to the serine-threonine kinase family,which plays a pivotal role in regulating the damage,survival,axon guidance,and regeneration of neurons.ROCKs are also involved in the biological effects of immune cells and glial cells,as well as the development of neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and multiple sclerosis.Previous studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the abovementioned neurodegenerative diseases by inhibiting neuroinflammation,regulating immune imbalance,repairing the blood-brain barrier,and promoting nerve repair and myelin regeneration.Fasudil,the first ROCKs inhibitor to be used clinically,has a good therapeutic effect on neurodegenerative diseases.Fasudil increases the activity of neural stem cells and mesenchymal stem cells,thus optimizing cell therapy.This review will systematically describe,for the first time,the effects of abnormal activation of ROCKs on T cells,B cells,microglia,astrocytes,oligodendrocytes,and pericytes in neurodegenerative diseases of the central nervous system,summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases,and clarify the possible cellular and molecular mechanisms of ROCKs inhibition.This review also proposes that fasudil is a novel potential treatment,especially in combination with cell-based therapy.Findings from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases.展开更多
Environmental cues provided by products from the diet,gut microbiota metabolism,and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome...Environmental cues provided by products from the diet,gut microbiota metabolism,and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome of multiple sclerosis(MS),an autoimmune disease of the central nervous system(CNS),1 which affects approximately 2.3 million people worldwide.2 Among these receptors,the ligand-activated transcription factor retinoic acid receptorα(RAR-α)senses retinoic acid and other ligands to promote the transcription of genes that have retinoic acid receptor elements in their promoter region.3 Supplementation with all-trans retinoic acid(ATRA),a metabolite of vitamin A,ameliorates inflammation in MS and the corresponding animal model,experimental autoimmune encephalomyelitis(EAE),by shifting the balance between Th17/regulatory T cells(Tregs)and inducing tolerogenic dendritic cells.4,5 To overcome the weaknesses associated with ATRA agonists,e.g.,instability,poor bioavailability and nonselective binding to a broad range of retinoid receptors,a variety of synthetic agonists specifically targeting RAR have been developed.6 One of them,AM80,inhibits Th17 cells and suppress acute neuroinflammation;however,continuous AM80 treatment is ineffective,most likely because AM80 also inhibits Tregs and IL-10 production.6 AM580,a stable benzoic derivative of retinoic acid and a selective RAR-αagonist,has been recently shown to significantly reduce the production of Th1 cytokines but promote Th2 cytokines in human PBMCs7 and to inhibit microglial activation,thus acting beneficially in Alzheimer’s disease treatment.8 In addition,AM580 protects retinal cells against diabetes-induced apoptosis by inducing neurotrophic factors.9 However,whether it has a protective effect on neuroinflammation is unknown.展开更多
基金supported by the National Natural Science Foundation of China,Nos. 82004028 (to LJS) and 81473577 (to CGM)China Postdoctoral Science Foundation,No. 2020M680912 (to LJS)+4 种基金Shanxi Applied Basic Research Project,No. 201901D211538 (to LJS)Leading Team of Medical Science and Technology of Shanxi Province,No. 2020TD05 (to CGM)Funds for Construction of Key Disciplines from Shanxi University of Chinese Medicine,Young Scientists Cultivation Project of Shanxi University of Chinese Medicine No. 2021PYQN-09 (to LJS)Basic Research Project of the Cultivation Plan of Scientific and Technological Innovation Ability of Shanxi University of Chinese Medicine,No. 2020PY-JC-02 (to LJS)Cardiovascular Special Fund Project of National Regional Traditional Chinese Medicine Medical Center of Affiliated Hospital of Shanxi University of Chinese Medicine in 2021, No. XGZX202115 (to LJS)。
文摘Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer’s disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes;these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer’s disease. Our literature search found that phenotypic changes occur continuously in Alzheimer’s disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer’s disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer’s disease.
基金supported partially by the National Natural Science Foundation of China,No.81473577(to CGM)a grant from the Department of Science and Technology of Shanxi Province,China,No.201803D421073(to YQY)and No.201805D111009(to CGM)+2 种基金a grant from Shanxi Applied Basic Research Project,No.201901D211538(to LJS)Datong Bureau of Science and Technology of China,No.2019198(to CGM)Research Project Funds from Shanxi Scholarship Council of China,No.2014-7(to CGM)。
文摘Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, and sustaining neuroprotective effects. Astrocytes become activated as a result of inflammatory responses during the progression of pathological changes associated with neurodegenerative disorders. Reactive astrocytes(neurotoxic A1 and neuroprotective A2) are triggered during disease progression and pathogenesis due to neuroinflammation and ischemia. However, only a limited body of literature describes morphological and functional changes of astrocytes during the progression of neurodegenerative diseases. The present review investigated the detrimental and beneficial roles of astrocytes in neurodegenerative diseases reported in recent studies, as these cells have promising therapeutic potential and offer new approaches for treatment of neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China, Nos.81473577 (to CGM), 81903596 (to QW), 82004028 (to LJS)China Postdoctoral Science Foundation, No.2020M680912 (to LJS)+2 种基金Open Project of The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education of China,No.2019004 (to CGM)Science and Technology Innovation Project of Shanxi Colleges of China, Nos.2019L0728 (to QW)Cultivation Project of Shanxi Universtity of Chinese Medicine of China, No.2019PY130 (to QW)
文摘Ras homolog(Rho)-associated kinases(ROCKs)belong to the serine-threonine kinase family,which plays a pivotal role in regulating the damage,survival,axon guidance,and regeneration of neurons.ROCKs are also involved in the biological effects of immune cells and glial cells,as well as the development of neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and multiple sclerosis.Previous studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the abovementioned neurodegenerative diseases by inhibiting neuroinflammation,regulating immune imbalance,repairing the blood-brain barrier,and promoting nerve repair and myelin regeneration.Fasudil,the first ROCKs inhibitor to be used clinically,has a good therapeutic effect on neurodegenerative diseases.Fasudil increases the activity of neural stem cells and mesenchymal stem cells,thus optimizing cell therapy.This review will systematically describe,for the first time,the effects of abnormal activation of ROCKs on T cells,B cells,microglia,astrocytes,oligodendrocytes,and pericytes in neurodegenerative diseases of the central nervous system,summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases,and clarify the possible cellular and molecular mechanisms of ROCKs inhibition.This review also proposes that fasudil is a novel potential treatment,especially in combination with cell-based therapy.Findings from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases.
基金supported by the NIH grants NS099594 and AI135601.Q.W.and C.G.M.supported by grants from the National Natural Science Foundation of China(No.81371414 and 81473577)。
文摘Environmental cues provided by products from the diet,gut microbiota metabolism,and exposure to sunlight are sensed by specific receptors that drive a specific genomic profile in immune cells and influence the outcome of multiple sclerosis(MS),an autoimmune disease of the central nervous system(CNS),1 which affects approximately 2.3 million people worldwide.2 Among these receptors,the ligand-activated transcription factor retinoic acid receptorα(RAR-α)senses retinoic acid and other ligands to promote the transcription of genes that have retinoic acid receptor elements in their promoter region.3 Supplementation with all-trans retinoic acid(ATRA),a metabolite of vitamin A,ameliorates inflammation in MS and the corresponding animal model,experimental autoimmune encephalomyelitis(EAE),by shifting the balance between Th17/regulatory T cells(Tregs)and inducing tolerogenic dendritic cells.4,5 To overcome the weaknesses associated with ATRA agonists,e.g.,instability,poor bioavailability and nonselective binding to a broad range of retinoid receptors,a variety of synthetic agonists specifically targeting RAR have been developed.6 One of them,AM80,inhibits Th17 cells and suppress acute neuroinflammation;however,continuous AM80 treatment is ineffective,most likely because AM80 also inhibits Tregs and IL-10 production.6 AM580,a stable benzoic derivative of retinoic acid and a selective RAR-αagonist,has been recently shown to significantly reduce the production of Th1 cytokines but promote Th2 cytokines in human PBMCs7 and to inhibit microglial activation,thus acting beneficially in Alzheimer’s disease treatment.8 In addition,AM580 protects retinal cells against diabetes-induced apoptosis by inducing neurotrophic factors.9 However,whether it has a protective effect on neuroinflammation is unknown.