Function and therapeutic value of astrocytes in neurological diseases

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(5), P. 339 - 358

Published: Feb. 16, 2022

Language: Английский

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Revisiting the critical roles of reactive astrocytes in neurodegeneration

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(7), P. 2697 - 2706

Published: April 10, 2023

Language: Английский

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Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 2, 2024

Abstract Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence PD remains to be defined. Methods Long culture-induced replicative model 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature model, mouse of were investigate the metformin vivo vitro. Immunofluorescence staining flow cytometric analyses performed evaluate mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA substantia nigra pars compacta regions specifically reduce astrocytic cGAS expression clarify potential molecular mechanism by which inhibited PD. Results showed that vitro mice. Mechanistically, normalized function DNA release through mitofusin 2 (Mfn2), leading inactivation cGAS-STING, delayed prevented neurodegeneration. Mfn2 overexpression reversed inhibitory role cGAS-STING activation senescence. More importantly, ameliorated dopamine neuron injury behavioral deficits mice reducing accumulation senescent via inhibition activation. Deletion abolished suppressive Conclusions This work reveals delays inhibiting Mfn2-cGAS suggest is promising therapeutic agent diseases.

Language: Английский

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Homer1 promotes the conversion of A1 astrocytes to A2 astrocytes and improves the recovery of transgenic mice after intracerebral hemorrhage

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: March 14, 2022

Inflammation induced by intracerebral hemorrhage (ICH) is one of the main causes high mortality and poor prognosis patients with ICH. A1 astrocytes are closely associated neuroinflammation neurotoxicity, whereas A2 neuroprotective. Homer scaffolding protein 1 (Homer1) plays a protective role in ischemic encephalopathy neurodegenerative diseases. However, Homer1 ICH-induced inflammation effect on phenotypic conversion remain unknown.Femoral artery autologous blood from C57BL/6 mice was used to create an ICH model. We use phenotype marker C3 S100A10 detect astrocyte after overexpression/knock-down were constructed adeno-associated virus (AAV) infection explore its mechanism action Finally, selumetinib injected into situ sites brains Homer1flox/flox/Nestin-Cre+/- study efficacy treatment using mouse cytokine array potential mechanism.The expression peaked third day colocalized astrocytes. promotes vivo vitro. Overexpression inhibits activation MAPK signaling, knock-down increases pathway-related proteins. The selumetinib, non-ATP competitive MEK1/2 inhibitor, improved outcome mice. reduced inflammatory factor TNFSF10 increased anti-inflammatory factors activin A, persephin, TWEAK.Homer1 important inhibiting suppressing In injection may be novel effective method for

Language: Английский

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Reducing complement activation during sleep deprivation yields cognitive improvement by dexmedetomidine

British Journal of Anaesthesia, Journal Year: 2023, Volume and Issue: 131(3), P. 542 - 555

Published: July 29, 2023

Sleep loss and its associated conditions (e.g. cognitive deficits) represent a large societal burden, but the underlying mechanisms of these deficits remain unknown. This study assessed effect dexmedetomidine (DEX) on decline induced by sleep loss.C57BL/6 mice were subjected to chronic restriction (CSR) for 20 h (5 pm-1 pm next day) daily 7 days, tests subsequently carried out. The neuromolecular cellular changes that occurred in presence absence DEX (100 μg kg-1, i.v., at 1 3 every also investigated.CSR displayed learning memory 12% (P<0.05) Y-maze 18% (P<0.01) novel object recognition test; with increases microglial activation, CD68+ phagosome counts, astrocyte-derived complement C3 secretion, C3a receptor expression (all P<0.05). Synapse elimination, as indicated 66% decrease synaptophysin (P=0.0004) 45% postsynaptic density protein-95 (P=0.0003), was occurrence deficits. activated astrocytic α2A adrenoceptors inhibited release attenuate synapse elimination through phagocytosis. restored synaptic connections reversed CSR.The results demonstrate pathway activation contributes loss-related protects against deprivation-induced activation. Dexmedetomidine holds potential preventing loss, which warrants further study.

Language: Английский

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The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson’s disease via LCN2-dependent astrocyte senescence

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(10), P. 2280 - 2292

Published: Aug. 26, 2023

Language: Английский

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Potassium Channels in Parkinson’s Disease: Potential Roles in Its Pathogenesis and Innovative Molecular Targets for Treatment

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 75(4), P. 758 - 788

Published: March 14, 2023

Parkinson9s disease (PD) is a neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region midbrain. The results subsequent reduction dopamine striatum, which underlies core motor symptoms PD. To date, there are no effective treatments to stop, slow, or reverse pathological progression neurodegeneration. This unfortunate predicament because current early stages understanding biological targets and pathways involved PD pathogenesis. Ion channels have become emerging for new therapeutic development due their essential roles neuronal function neuroinflammation. Potassium most prominent ion channel family been shown be critically important pathology modulating excitability, neurotransmitter release, synaptic transmission, In this review, members subfamilies voltage-gated K⁺ channels, inward rectifying Ca²⁺-activated potassium described. Evidence role these aetiology discussed together with latest views on related mechanisms potential as developing neuroprotective drugs Significance Statement second common disorder, featuring progressive degeneration It multifactorial involving multiple risk factors complex pathobiological mechanisms. Mounting evidence suggests that play vital pathogenesis regulating excitability immune cell function. Therefore, they "hot" PD, demonstrated clinical trials drug candidates targeting therapy.

Language: Английский

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Ion Channel Dysfunction in Astrocytes in Neurodegenerative Diseases

Frontiers in Physiology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 9, 2022

Astrocytes play an important role in the central nervous system (CNS). Ion channels these cells not only function ion transport, and maintain water/ion metabolism homeostasis, but also participate physiological processes of neurons glial by regulating signaling pathways. Increasing evidence indicates channel proteins astrocytes, such as aquaporins (AQPs), transient receptor potential (TRP) channels, adenosine triphosphate (ATP)-sensitive potassium (K-ATP) P2X7 receptors (P2X7R), are strongly associated with oxidative stress, neuroinflammation characteristic neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD) amyotrophic lateral sclerosis (ALS). Since protein dysfunction is a significant pathological feature astrocytes diseases, we discuss critical their pathways order to understand underlying molecular mechanisms, which may yield new therapeutic targets for disorders.

Language: Английский

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Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte–microglia C3-C3aR pathway

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(4)

Published: April 22, 2023

Abstract Parkinson’s disease (PD) is the most common progressive neurodegenerative movement disorder, which characterized by dopaminergic (DA) neuron death and aggregation of neurotoxic α-synuclein. Cntnap4 , a risk gene autism, has been implicated to participate in PD pathogenesis. Here we showed lacking exacerbates α-synuclein pathology, nigrostriatal DA degeneration motor impairment, induced injection adeno-associated viral vector (AAV)-mediated human overexpression (AAV- h α-Syn). This scenario was further validated A53T transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, derived from damaged stimulates astrocytes release complement C3, activating microglial C3a receptor (C3aR), turn triggers microglia secrete C1q pro-inflammatory cytokines. Thus, astrocyte–microglia crosstalk drives dysfunction PD. Furthermore, that vivo depletion targeted delivery novel C3aR antagonist (SB290157) rescue aggravated pathology resulting lacking. Together, our results indicate plays key role pathogenesis regulating glial may be potential target for treatment.

Language: Английский

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Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After Ischemic Stroke

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(12), P. 10246 - 10270

Published: May 7, 2024

Language: Английский

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