The gut microbiome modulates the transformation of microglial subtypes DOI Creative Commons
Yu Huang, Jing Wu,

Hanping Zhang

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(4), P. 1611 - 1621

Published: March 13, 2023

Abstract Clinical and animal studies have shown that gut microbiome disturbances can affect neural function behaviors via the microbiota–gut–brain axis, may be implicated in pathogenesis of several brain diseases. However, exactly how modulates nervous system activity remains obscure. Here, using a single-cell nucleus sequencing approach, we sought to characterize cell type–specific transcriptomic changes prefrontal cortex hippocampus derived from germ-free (GF), specific pathogen free, colonized-GF mice. We found absence microbiota resulted cell-specific changes. Furthermore, microglia transcriptomes were preferentially influenced, which could effectively reversed by microbial colonization. Significantly, modulated mutual transformation microglial subpopulations two regions. Cross-species analysis showed transcriptome these mainly associated with Alzheimer’s disease (AD) major depressive disorder (MDD), further supported behavioral tests. Our findings demonstrate modulate subtypes, lead new insights into AD MDD.

Language: Английский

The “Neuro-Glial-Vascular” Unit: The Role of Glia in Neurovascular Unit Formation and Dysfunction DOI Creative Commons
Elisabeth Kugler, John A. Greenwood, Ryan B. MacDonald

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Sept. 27, 2021

The neurovascular unit (NVU) is a complex multi-cellular structure consisting of endothelial cells (ECs), neurons, glia, smooth muscle (SMCs), and pericytes. Each component closely linked to each other, establishing structural functional unit, regulating central nervous system (CNS) blood flow energy metabolism as well forming the blood-brain barrier (BBB) inner blood-retina (BRB). As name suggests, "neuro" "vascular" components NVU are recognized coupling key function NVU. However, consists multiple cell types its functionality goes beyond resulting coupling, with cross-component links signaling, metabolism, homeostasis. Within NVU, glia have gained increased attention it increasingly clear that they fulfill various multi-level functions in Glial dysfunctions were shown precede neuronal vascular pathologies suggesting roles for pathogenesis disease. In this review, we take "glio-centric" view on development retina brain, how these change disease, advancing experimental techniques will help us address unanswered questions.

Language: Английский

Citations

131
Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques DOI Creative Commons
Ethan R. Roy,

Gabriel S. Chiu,

Sanming Li

et al.

Immunity, Journal Year: 2022, Volume and Issue: 55(5), P. 879 - 894.e6

Published: April 19, 2022

Language: Английский

Citations

131
Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice DOI Creative Commons
Shanshan Li, Yinquan Fang, Yihe Zhang

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 41(4), P. 111532 - 111532

Published: Oct. 1, 2022

The function and regulation of different heterogeneous reactive states astrocytes in depression remain unclear. Here, we demonstrate that neurotoxic (A1-like) are strongly induced, prior to behavioral impairments dendritic atrophy, depression-like mice. More interestingly, global or microglia-specific knockout Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific Nlrp3 depletion is ineffective. Microglial ablation also alleviates the neuronal dysfunction induced by both vitro vivo. We further show microglia NF-κB pathway activates NLRP3 inflammasome which turn caspase-1 induce secretion A1 inductors, leading production astrocytes. Altogether, this study reveals microglial induction via activating neuroinflammatory response chronic stress suggests a potential therapeutic strategy for depression.

Language: Английский

Citations

113
Insights into Alzheimer’s disease from single-cell genomic approaches DOI
Mitchell H. Murdock, Li‐Huei Tsai

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(2), P. 181 - 195

Published: Jan. 2, 2023

Language: Английский

Citations

98
CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states DOI
Kun Leng, Indigo V.L. Rose, Hyosung Kim

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(11), P. 1528 - 1542

Published: Oct. 27, 2022

Language: Английский

Citations

95
Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin DOI Creative Commons
Hyosung Kim, Kun Leng, Jinhee Park

et al.

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 2, 2022

Abstract Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation astrocytes to reactive states can be protective or harmful BBB Here, using a human induced pluripotent stem cell (iPSC)-derived co-culture model, we show tumor necrosis factor (TNF) transitions an inflammatory state causes dysfunction through activation STAT3 and increased expression SERPINA3 , which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, correlated astrocytic vascular inflammation in postmortem tissue. Further, murine brain organotypic cultures, astrocyte-specific silencing Serpina3n reduced after TNF challenge. Last, treatment with recombinant both ex vivo explant cultures was sufficient induce dysfunction-related molecular changes. Overall, our results define TNF-STAT3-α1ACT signaling axis as driver astrocyte signature contributes dysfunction.

Language: Английский

Citations

95
Lipid-accumulated reactive astrocytes promote disease progression in epilepsy DOI
Zhang‐Peng Chen,

Suji Wang,

Xiansen Zhao

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(4), P. 542 - 554

Published: March 20, 2023

Language: Английский

Citations

93
The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis DOI Creative Commons
Monokesh Kumer Sen, David A. Mahns, Jens R. Coorssen

et al.

Glia, Journal Year: 2022, Volume and Issue: 70(7), P. 1215 - 1250

Published: Feb. 2, 2022

Abstract In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site by microglia is critically important to achieve adequate slow progression disease. However, how phagocytose debris, why impaired in MS, not fully known; likewise, role remains unclear. Recent studies using cuprizone (CPZ) animal model central nervous system revealed that up‐regulation signaling proteins facilitates effective phagocytosis debris. Moreover, during demyelination, protective mediators are released activated microglia, resulting acceleration CPZ model. contrast, inadequate microglial activation or recruitment production toxic mediators, impairs demyelination. addition microglia‐mediated phagocytosis, astrocytes play phagocytic process recruiting producing regenerative mediators. current review update these emerging findings model, discussing roles myelination.

Language: Английский

Citations

92
Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain DOI Creative Commons
Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Jan. 10, 2022

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed information processing and memory. This long-COVID cognitive syndrome shares many features with the cancer therapy-related (CRCI). Neuroinflammation, particularly microglial reactivity consequent dysregulation hippocampal neurogenesis oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute persistent symptoms associated even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by - without neuroinvasion effects on oligodendroglial lineage. Using a mouse model induced intranasal delivery, found white matter-selective reactivity, pattern observed Human brain tissue from 9 individuals COVID-19 or exhibits same prominent reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among chemokines demonstrating elevation CCL11, which impairments function. Humans experiencing (48 subjects) similarly demonstrate CCL11 levels compared those who lack (15 subjects). Impaired neurogenesis, decreased oligodendrocytes myelin loss subcortical matter evident 1 week, persisted until 7 weeks, following mice. Taken together, findings presented here illustrate striking similarities between neuropathophysiology after therapy infection, elucidate deficits lasting

Language: Английский

Citations

91
Neuroinflammation: An astrocyte perspective DOI Open Access
Hong‐Gyun Lee, Joon-Hyuk Lee, Lucas E. Flausino

et al.

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(721)

Published: Nov. 8, 2023

Astrocytes are abundant glial cells in the central nervous system (CNS) that play active roles health and disease. Recent technologies have uncovered functional heterogeneity of astrocytes their extensive interactions with other cell types CNS. In this Review, we highlight intricate between astrocytes, CNS-resident cells, CNS-infiltrating as well potential therapeutic value context inflammation neurodegeneration.

Language: Английский

Citations

82