Neuropilin-1 Mediates SARS-CoV-2 Infection of Astrocytes in Brain Organoids, Inducing Inflammation Leading to Dysfunction and Death of Neurons

mBio, Journal Year: 2022, Volume and Issue: 13(6)

Published: Oct. 31, 2022

Coronavirus disease 2019 (COVID-19) is frequently associated with neurological deficits, but how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces these effects remains unclear. Here, we show that astrocytes are readily infected by SARS-CoV-2, surprisingly, neuropilin-1, not angiotensin-converting enzyme (ACE2), serves as the principal receptor mediating cell entry. Infection further positively modulated two-pore segment channel (TPC2) protein regulates membrane trafficking and endocytosis. Astrocyte infection produces a pathological response closely resembling reactive astrogliosis characterized elevated type I interferon (IFN) production, increased inflammation, decreased expression of transporters water, ions, choline, neurotransmitters. These combined events initiated within produce hostile microenvironment promotes dysfunction death uninfected bystander neurons.

Language: Английский

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The role of astrocyte structural plasticity in regulating neural circuit function and behavior

Glia, Journal Year: 2022, Volume and Issue: 70(8), P. 1467 - 1483

Published: May 10, 2022

Abstract Brain circuits undergo substantial structural changes during development, driven by the formation, stabilization, and elimination of synapses. Synaptic connections continue to experience‐dependent rearrangements throughout life, which are postulated underlie learning memory. Astrocytes, a major glial cell type in brain, physically contact with synaptic through their ensheathment Astrocytes strongly contribute remodeling structures healthy diseased central nervous systems regulating connectivity behaviors. However, whether plasticity astrocytes is involved critical functions at synapse unknown. This review will discuss emerging evidence linking astrocytic circuit regulation Moreover, we survey possible molecular cellular mechanisms non‐cell‐autonomous effects on neuronal plasticity. Finally, how astrocyte morphological different physiological states disease conditions function dysfunction.

Language: Английский

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Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

JAMA Neurology, Journal Year: 2023, Volume and Issue: 80(11), P. 1209 - 1209

Published: Oct. 9, 2023

Importance Factors associated with synapse loss beyond amyloid-β plaques and neurofibrillary tangles may more closely correlate the emergence of cognitive deficits in Alzheimer disease (AD) be relevant for early therapeutic intervention. Objective To investigate whether accumulation tau oligomers synapses is excessive elimination by microglia or astrocytes outcomes (dementia vs no dementia [hereinafter termed resilient]) individuals equal burdens AD neuropathologic changes at autopsy. Design, Setting, Participants This cross-sectional postmortem study included 40 human brains from Massachusetts Disease Research Center Brain Bank Braak III to IV stages pathology but divergent antemortem cognition resilient) cognitively normal controls negligible changes. The visual cortex, a region without tangle deposition stages, was assessed after expansion microscopy analyze spatial relationships astrocytes. were matched age, sex, apolipoprotein E status. Evidence Lewy bodies, TDP-43 aggregates, other lesions different neuropathology exclusion criteria. Tissue collected July 1998 November 2020, analyses conducted February 1, 2022, through May 31, 2023. Main Outcomes Measures Amyloid-β plaques, neuropil thread burden, density, synapses, internalization oligomer–tagged quantitated. Analyses performed using 1-way analysis variance parametric variables Kruskal-Wallis test nonparametric variables; between-group differences evaluated Holm-Šídák tests. Results Of participants (mean [SD] age death, 88 [8] years; 21 [52%] male), 19 had early-stage IV, 13 resilient similar 8 (Braak 0-II). Brains not substantial presynaptic (43%), postsynaptic (33%), colocalized mature synaptic elements (38%) compared significantly higher percentages internalized IBA1-positive [SD], 13.3% [3.9%] 2.6% [1.9%] 0.9% [0.5%] control; P < .001) GFAP-positive 17.2% [10.9%] 3.7% [4.0%] 2.7% [1.8%] = .001). In brains, often proportions oligomer–containing inside presynapses, mean 7.4% 5.1% [0.8%] .006; postsynapses 11.6% [3.6%] 6.8% [1.3%] [2.5%] 7.0% [2.1%] 4.3% [2.2%] 4.0% [0.7%] .001; postsynapses, 7.9% 5.3% 3.0% [1.5%] increased controls. Those occurred absence cortex. Conclusion Relevance findings this suggest that excessively engulf abnormal presence serve as signals glial-mediated brain function AD.

Language: Английский

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Neuron-astrocyte omnidirectional signaling in neurological health and disease

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: June 8, 2023

Astrocytes are an abundantly distributed population of glial cells in the central nervous system (CNS) that perform myriad functions normal and injured/diseased brain. exhibit heterogeneous phenotypes response to various insults, a process known as astrocyte reactivity. The accuracy precision brain signaling primarily based on interactions involving neurons, astrocytes, oligodendrocytes, microglia, pericytes, dendritic within CNS. have emerged critical entity because their unique role recycling neurotransmitters, actively modulating ionic environment, regulating cholesterol sphingolipid metabolism, influencing cellular crosstalk diverse neural injury conditions neurodegenerative disorders. However, little is about how synapse formation, axon specification, neuroplasticity, homeostasis, network activity following dynamic surveillance, CNS structure neurological diseases. Interestingly, tripartite hypothesis came light fill some knowledge gaps constitute interaction subpopulation synapses. This review highlights astrocytes' health neurological/neurodegenerative diseases arising from omnidirectional between astrocytes neurons at synapse. also recapitulates disruption with focus perturbations homeostatic astrocytic function key driver modulate molecular physiological processes toward

Language: Английский

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Cx43 hemichannels contribute to astrocyte-mediated toxicity in sporadic and familial ALS

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(13)

Published: March 21, 2022

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions contribute to astrocyte-mediated neurotoxicity amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 a mouse model ALS slows disease progression both spatially temporally, provides motor neuron (MN) protection, improves survival. In addition, expression is up-regulated human postmortem tissue cerebrospinal fluid from patients. Using induced pluripotent stem cell–derived astrocytes (hiPSC-A) familial sporadic ALS, establish Cx43-hemichannels are enriched at membrane. We also demonstrate pharmacological blockade using GAP 19, mimetic peptide blocker, tonabersat, clinically tested small molecule, neuroprotection hiPSC-MN reduces neuronal hyperexcitability. Extending vitro application tonabersat with chronic administration SOD1G93A mice results MN protection reduction reactive astrocytosis microgliosis. Taking these data together, our studies identify as conduits target for disease-modifying therapies.

Language: Английский

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Foundations and implications of astrocyte heterogeneity during brain development and disease

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(9), P. 692 - 703

Published: July 23, 2022

Language: Английский

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COVID-19 and olfactory dysfunction: a looming wave of dementia?

Journal of Neurophysiology, Journal Year: 2022, Volume and Issue: 128(2), P. 436 - 444

Published: July 27, 2022

Olfactory dysfunction is a hallmark symptom of COVID-19 disease resulting from the SARS-CoV-2 virus. The cause sudden and usually temporary anosmia that most people suffer likely entirely peripheral-inflammation other damage caused by virus in sensory epithelium inside upper recesses nasal cavity can or prevent chemicals properly activating olfactory neurons. However, persistent COVID-19, form hyposmia parosmia (decreased altered smell) may affect as many 15 million worldwide. This epidemic thus continuing public health concern. Mounting evidence suggests itself inflammation immune response invade bulb, via non-neuronal transmission. COVID-19-related long-term early to limbic brain regions suggest pattern degeneration similar seen stages Alzheimer's disease, Parkinson's Lewy body dementia. Thus, coupled with cognitive emotional disturbance be first signs delayed onset dementia neurodegeneration. Few treatments are known effective further degeneration, but line defense against environmental enrichment. There pressing need for more research on longitudinal studies including function patients who have recovered even mild COVID-19.

Language: Английский

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Maternal immune activation and role of placenta in the prenatal programming of neurodevelopmental disorders

Neuronal Signaling, Journal Year: 2023, Volume and Issue: 7(2)

Published: May 17, 2023

Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence support these mechanistic links, with placental inflammatory responses dysregulation function implicated. This leads changes in fetal brain balance altered epigenetic regulation key pathways. The prenatal timing such mIA-evoked changes, accompanying developmental an

Language: Английский

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Neuronal and astrocyte determinants of critical periods of plasticity

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(7), P. 566 - 580

Published: May 16, 2023

Language: Английский

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Outdoor air pollution and brain development in childhood and adolescence

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(8), P. 593 - 607

Published: July 24, 2024

Language: Английский

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