Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders

Cold Spring Harbor Perspectives in Biology, Год журнала: 2024, Номер 16(7), С. a041356 - a041356

Опубликована: Фев. 5, 2024

In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond CNS damage and disease through a process called "reactivity." Recent evidence reveals that astrocyte reactivity is heterogeneous spectrum of potential changes occur context-specific manner. These are determined by diverse signaling events vary not only with nature severity different insults but also location CNS, genetic predispositions, age, potentially "molecular memory" previous events. Astrocyte can be associated both essential beneficial as well harmful effects. The available information rapidly expanding much has been learned about molecular diversity reactivity. Emerging functional associations point toward roles for determining outcome disorders.

Язык: Английский

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Reactive astrocytes associated with prion disease impair the blood brain barrier

Neurobiology of Disease, Год журнала: 2023, Номер 185, С. 106264 - 106264

Опубликована: Авг. 18, 2023

Impairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases. In disease, increased BBB permeability was reported 40 years ago, yet mechanisms behind loss integrity have never been explored. Recently, we showed that reactive astrocytes associated with diseases are neurotoxic. The current work examines potential link between astrocyte reactivity breakdown. prion-infected mice, aberrant localization aquaporin 4 (AQP4), sign retraction astrocytic endfeet from blood vessels, were noticeable prior disease onset. Gaps in cell-to-cell junctions along together downregulation Occludin, Claudin-5 VE-cadherin, which constitute tight adherens junctions, suggested linked degeneration vascular endothelial cells. contrast cells isolated non-infected adult originating mice displayed disease-associated changes, lower levels VE-cadherin expression, impaired reduced trans-endothelial electrical resistance (TEER). Endothelial when co-cultured animals or treated media conditioned by astrocytes, developed phenotype observed mice. Reactive found produce high secreted IL-6, treatment monolayers recombinant IL-6 alone their TEER. Remarkably, extracellular vesicles produced normal partially reversed animals. To our knowledge, first illustrate early breakdown document detrimental integrity. Moreover, findings suggest harmful effects proinflammatory factors astrocytes.

Язык: Английский

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Crosstalk between peripheral inflammation and brain: focus on the responses of microglia and astrocytes to peripheral challenge

Neurochemistry International, Год журнала: 2024, Номер unknown, С. 105872 - 105872

Опубликована: Окт. 1, 2024

Язык: Английский

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Astrocytic CREB in nucleus accumbens promotes susceptibility to chronic stress

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 16, 2024

Abstract Background Increasing evidence implicates astrocytes in stress and depression both rodent models human Major Depressive Disorder (MDD). Despite this, little is known about the transcriptional responses to of within nucleus accumbens (NAc), a key brain reward region, their influence on behavioral outcomes. Methods We used whole cell sorting, RNA-sequencing, bioinformatic analyses investigate NAc astrocyte transcriptome male mice response chronic social defeat (CSDS). Immunohistochemistry was determine stress-induced changes astrocytic CREB NAc. Finally, regulation depression-like behavior investigated using viral-mediated manipulation combination with CSDS. Results found robust CSDS stressed mice, seen stress-susceptible stress-resilient animals. Bioinformatic analysis revealed CREB, transcription factor widely studied neurons, as one top-predicted upstream regulators transcriptome, opposite activation states resilient versus susceptible mice. This result confirmed at protein level immunohistochemistry. Viral overexpression selectively promoted susceptibility stress. Conclusions Together, our data demonstrate that responds robustly and, for first time, contributes depressive-like behaviors. A better understanding may reveal unknown molecular mechanisms underlying neuropsychiatric disorders.

Язык: Английский

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Engulfment of viable neurons by reactive microglia in prion diseases

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 9, 2024

Abstract Microglia are recognized as the main cells in central nervous system responsible for phagocytosis. During brain development, microglia eliminate excessive synapses and neurons, whereas normal aging neurodegenerative diseases, clearing protein aggregates cell debris. The current study demonstrates that prion disease, effectively phagocytose prions or PrP Sc during early preclinical stages. However, late stage, a critical shift occurs microglial activity from uptake to engulfment of neurons. This change before manifestation clinical symptoms is followed by rapid accumulation total , suggesting potential link neuronal dysfunction behavioral deficits. Surprisingly, engulfed neurons do not show apoptotic markers, indicating targeting viable Despite up 40% being partially at there no significant loss, many events incomplete, terminated protracted. phenomenon partial reactive independent CD11b pathway, previously associated with phagocytosis newborn neurodevelopment. establishes consistent occurrence across multiple prion-affected regions, various mouse-adapted strains, different subtypes sporadic Creutzfeldt-Jakob disease (sCJD) humans. work describes new microglia, shedding light on novel aspect neuronal-microglia interactions.

Язык: Английский

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Glioprotective Effects of Sulforaphane in Hypothalamus: Focus on Aging Brain

Neurochemical Research, Год журнала: 2024, Номер 49(9), С. 2505 - 2518

Опубликована: Июнь 17, 2024

Язык: Английский

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Multiple steps of prion strain adaptation to a new host

Frontiers in Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Янв. 31, 2024

The transmission of prions across species is a critical aspect their dissemination among mammalian hosts, including humans. This process often necessitates strain adaptation. In this study, we sought to investigate the mechanisms underlying prion adaptation while mitigating biases associated with history cross-species natural strains. To achieve this, utilized synthetic hamster S05. Propagation S05 using mouse PrP C in Protein Misfolding Cyclic Amplification did not immediately overcome barrier. finding underscores involvement factors beyond disparities primary protein structures. Subsequently, performed five serial passages stabilize incubation time disease mice. levels Sc increased each passage, reaching maximum at third and declining thereafter. suggests that only initial stage primarily driven by an acceleration replication. During protracted new host, observed significant alterations glycoform ratio sialylation status N-glycans. These changes support notion qualitative modifications contribute more rapid progression. Furthermore, consistent decline sialylation, cue for “eat me” signaling, newly adapted exhibited preferential colocalization microglia. contrast dynamics, intensity microglia activation continued increase after passage host. summary, our study elucidates host multi-step several factors.

Язык: Английский

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Reactive astrocytes in prion diseases: Friend or foe?

PLoS Pathogens, Год журнала: 2024, Номер 20(6), С. e1012286 - e1012286

Опубликована: Июнь 20, 2024

Язык: Английский

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Immunomorphologic assessment of changes in functional astroglial proteins in a kainate-induced hippocampal sclerosis model

Annals of Clinical and Experimental Neurology, Год журнала: 2024, Номер 18(2), С. 34 - 44

Опубликована: Июль 8, 2024

Introduction. Astrocytes are involved in mediator metabolism, neuroplasticity, energy support of neurons and neuroinflammation, this determines their pathogenetic role epilepsy. Aim. This study aimed at evaluating region-specific changes the distribution functional astroglial proteins reactive astrocytes a kainate-induced model mesial temporal lobe Materials methods. The localization expression (i.e. aquaporin-4, connexin-43, EAAT1/2, glutamine synthetase) hippocampus CA3 region, dentate gyrus, stratum lucidum layer were evaluated by immunofluorescence 28 days after intra-hippocampal administration kainic acid to animals. Results. Changes heterogeneous different hyppocampus subregions. associated with mossy fibers showed highest vulnerability decreased content and/or disturbed channels transporters that form membrane complexes processes. Disturbances homeostatic functions aggravated adverse processes both on side where toxin was injected contralateral hippocampus.

Язык: Английский

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Redistribution of the astrocyte phenotypes in the medial vestibular nuclei after unilateral labyrinthectomy

Frontiers in Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Июнь 26, 2023

Astrocytes are highly heterogeneous and involved in different aspects of fundamental functions the central nervous system (CNS). However, whether how this population cells reacts to pathophysiological challenge is not well understood. To investigate response status astrocytes medial vestibular nucleus (MVN) after loss, we examined subtypes MVN using single-cell sequencing technology a unilateral labyrinthectomy mouse model. We discovered four with each displaying unique gene expression profiles. After labyrinthectomy, proportion astrocytic their transcriptional features on ipsilateral side differ significantly from those contralateral side. With new markers detect classify MVN, our findings implicate potential roles adaptive changes astrocyte early compensation following peripheral damage reverse behavioral deficits.

Язык: Английский

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