Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS

Cells, Journal Year: 2022, Volume and Issue: 11(23), P. 3923 - 3923

Published: Dec. 4, 2022

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes' neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration SOD1G93A mice, but mechanisms are still unclear. We postulated that effects could be mediated by extracellular vesicles (EVs) secreted MSCs. investigated, immunohistochemical, molecular, vitro functional analyses, activity MSC-derived EVs on pathological astrocytes isolated from spinal cord symptomatic mice human (iAstrocytes) differentiated inducible neural progenitor cells (iNPCs) patients. In EV exposure rescued mouse towards MNs. significantly dampened neuroinflammation astrocytes. iAstrocytes, increased antioxidant factor Nrf2 reduced reactive oxygen species. previously found nine miRNAs upregulated EVs. Here, transfection single miRNA mimics activation expression neuroinflammatory factors. Moreover, miR-466q miR-467f downregulate Mapk11, while miR-466m-5p miR-466i-3p promote nuclear translocation Nrf2. miR-29b-3p mimic NQO1 modulate through anti-inflammatory antioxidant-shuttled miRNAs, thus representing therapeutic strategy ALS.

Language: Английский

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Oligodendrocytes and myelin: Active players in neurodegenerative brains?

Developmental Neurobiology, Journal Year: 2022, Volume and Issue: 82(2), P. 160 - 174

Published: Jan. 26, 2022

Oligodendrocytes (OLs) are a major type of glial cells in the central nervous system that generate multiple myelin sheaths to wrap axons. Myelin ensures fast and efficient propagation action potentials along axons supports neurons with nourishment. The decay OLs has been implicated age-related neurodegenerative diseases these changes generally considered as an inevitable result neuron loss axon degeneration. Noticeably, undergo dynamic healthy adult brains, is, newly formed continuously added throughout life from differentiation oligodendrocyte precursor (OPCs) pre-existing may degeneration or remodeling. Increasing evidence shown present early stages diseases, even prior significant neuronal functional deficits. More importantly, oligodendroglia-specific manipulation, by either deletion disease gene enhancement renewal, can alleviate impairments animal models. These findings underscore possibility not passively but actively involved play important role modulating function survival. In this review, we summarize recent work characterizing both brains discuss potential targeting oligodendroglial treating diseases.

Language: Английский

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Neuroinduction and neuroprotection co-enhanced spinal cord injury repair based on IL-4@ZIF-8-loaded hyaluronan–collagen hydrogels with nano-aligned and viscoelastic cues

Journal of Materials Chemistry B, Journal Year: 2022, Volume and Issue: 10(33), P. 6315 - 6327

Published: Jan. 1, 2022

Spontaneous recovery after spinal cord injury (SCI) is extremely limited since the severe inflammatory responses lead to secondary damage, and diseased extracellular matrix (ECM) fails provide inductive cues for nerve regeneration. To address these dilemmas, herein, we propose a biomaterial-based strategy combining neuroprotection neuroinduction SCI repair. Taking advantage of microfluidic chip, constructed imine-crosslinked aldehyde-methacrylate-hyaluronan/collagen hybrid hydrogel microfibers incorporating interleukin 4 (IL-4)-loaded ZIF-8 nanoparticles (IL4@ZIF-8 NPs). The possess pivotal traits mimicking natural ECM hold neuroinductive nanoalignment viscoelasticity, as well acidic microenvironment-responsive release neuroprotective IL-4. Then, elucidated role tailored in promoting structural functional rats. implanted IL4@ZIF-8 NPs protected endogenous neural cells by M2 polarization recruited macrophages suppressing inflammation. Additionally, enhanced neuronal differentiation, accelerated axonal regrowth, synapse formation remyelination, resulting from their ECM-mimicking oriented nano-topography viscoelasticity. Moreover, locomotor function was also improved cues. This work not only paves steps development novel class multifunctional hydrogels that manipulate tissue behavior modifying cellular microenvironment but provides intriguing insights repair even other central nervous system (CNS) injuries via engineering approaches.

Language: Английский

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The toxic metal hypothesis for neurological disorders

Frontiers in Neurology, Journal Year: 2023, Volume and Issue: 14

Published: June 23, 2023

Multiple sclerosis and the major sporadic neurogenerative disorders, amyotrophic lateral sclerosis, Parkinson disease, Alzheimer disease are considered to have both genetic environmental components. Advances been made in finding predispositions these but it has difficult pin down agents that trigger them. Environmental toxic metals implicated neurological since human exposure is common from anthropogenic natural sources, damaging properties suspected underlie many of disorders. Questions remain, however, as how enter nervous system, if one or combinations sufficient precipitate metal results different patterns neuronal white matter loss. The hypothesis presented here damage selective locus ceruleus neurons causes dysfunction blood-brain barrier. This allows circulating toxicants astrocytes, where they transferred to, damage, oligodendrocytes, neurons. type disorder arises depends on (i) which damaged, (ii) variants give rise susceptibility uptake, cytotoxicity, clearance, (iii) age, frequency, duration toxicant exposure, (iv) uptake various mixtures metals. Evidence supporting this presented, concentrating studies examined distribution system. Clinicopathological features shared between disorders listed can be linked Details provided applies multiple neurodegenerative Further avenues explore for suggested. In conclusion, may play a part several While further evidence support needed, protect system would prudent take steps reduce pollution industrial, mining, manufacturing burning fossil fuels.

Language: Английский

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Oligodendrocyte pathology in Huntington’s disease: from mechanisms to therapeutics

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(10), P. 802 - 816

Published: Aug. 15, 2023

Language: Английский

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Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Oct. 19, 2023

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, eventually death. Motor cortical hyperexcitability common phenomenon observed at presymptomatic stage ALS. Both cell-autonomous (the intrinsic properties neurons) non-cell-autonomous mechanisms (cells other than are believed to contribute hyperexcitability. Decoding pathological relevance these dynamic changes neurons glial cells has remained major challenge. This review summarizes evidence from clinical preclinical research, as well underlying mechanisms. We discuss potential role cells, particularly microglia, regulating abnormal neuronal activity during disease progression. Identifying early such system may provide new insights for earlier diagnosis ALS reveal novel targets halt

Language: Английский

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Inhibition of extracellular regulated kinase (ERK)-1/2 signaling pathway in the prevention of ALS: Target inhibitors and influences on neurological dysfunctions

European Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 100(7-8), P. 151179 - 151179

Published: Sept. 1, 2021

Cell signal transduction pathways are essential modulators of several physiological and pathological processes in the brain. During overactivation, these signaling may lead to disease progression. Abnormal protein kinase activation is associated with biological dysfunctions that facilitate neurodegeneration under different conditions. As a result, understanding brain disorders' development or Recent research findings indicate crucial role extracellular signal-regulated kinase-1/2 (ERK-1/2) during neuronal process. ERK-1/2 key component its mitogen-activated (MAPK) group, controlling certain neurological activities by regulating metabolic pathways, cell proliferation, differentiation, apoptosis. also influences elastic properties, nerve growth, cognitive processing injuries. The primary goal this review elucidate ERK1/2 signaling, which involved ALS-related neuropathological dysfunctions. ALS rare disorder category mainly affects cells responsible for voluntary muscle activity. progressive, means symptoms getting worse over time, there no cure effective treatment avoid reverse. Genetic abnormalities, oligodendrocyte degradation, glial immune deregulation Furthermore, current identifies inhibitors can promote neuroprotection neurotrophic effects against clinical-pathological presentation ALS. future, potential could be used related neurocomplications.

Language: Английский

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Neuronal–glial communication perturbations in murine SOD1G93A spinal cord

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Feb. 28, 2022

Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by proteinaceous aggregate accumulation and neuroinflammation culminating in rapidly progressive lower upper motor neuron death. To interrogate cell-intrinsic inter-cell type perturbations ALS, single-nucleus RNA sequencing was performed on the lumbar spinal cord murine ALS model SOD1G93A transgenic littermate control mice at peri-symptomatic onset stage of disease, age 90 days. This work uncovered perturbed tripartite synapse functions, complement activation metabolic stress affected cord; processes evidenced cell death proteolytic stress-associated gene sets. Concomitantly, these pro-damage events co-existed with dysregulated reparative mechanisms. provides a resource cell-specific niches asserts that interwoven dysfunctional neuronal-glial communications mediating neurodegeneration are underway prior to overt manifestation recapitulated, part, human post-mortem cord.

Language: Английский

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Chronic oligodendrocyte injury in central nervous system pathologies

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Nov. 19, 2022

Myelin, the membrane surrounding neuronal axons, is critical for central nervous system (CNS) function. Injury to myelin-forming oligodendrocytes (OL) in chronic neurological diseases (e.g. multiple sclerosis) ranges from sublethal lethal, leading OL dysfunction and myelin pathology, consequent deleterious impacts on axonal health that drive clinical impairments. This regulated by intrinsic factors such as heterogeneity age, extrinsic cellular molecular interactions. Here, we discuss responses of OLs injury, perspectives therapeutic targeting. We put forward targeting mature disease a promising strategy support CNS

Language: Английский

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Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review)

Experimental and Therapeutic Medicine, Journal Year: 2023, Volume and Issue: 27(1)

Published: Nov. 21, 2023

Parkinson's disease (PD) is a common neurodegenerative pathology whose major clinical symptoms are movement disorders. The main pathological characteristics of PD the selective death dopaminergic (DA) neurons in pars compacta substantia nigra and presence Lewy bodies containing α-synuclein (α-Syn) within these neurons. associated with numerous risk factors, including environmental genetic mutations aging. In many cases, complex interplay factors leads to onset PD. mutated α-Syn gene, which expresses pathologicalα-Syn protein, can cause Another important feature neuroinflammation, conducive neuronal death. able interact certain cell types brain, through phagocytosis degradation by glial cells, activation inflammatory pathways transmission between cells neurons, interactions peripheral immune α-Syn. addition aforementioned may also be aging, as prevalence increases advancing age. aging process impairs cellular clearance mechanism, chronic inflammation accumulation intracellular α-Syn, results DA present review, age-associated pathogenicity brain discussed facilitate understanding mechanisms pathogenesis, potentially provide insight for future treatment

Language: Английский

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