A Unique Type of Highly-Activated Microglia Evoking Brain Inflammation via Mif/Cd74 Signaling Axis in Aged Mice

Jin, Cheng‐Hao; Shao, Yijie; Zhang, Xiaotao; Xiang, Jiani; Zhang, Ruize; Sun, Zeyu; Mei, Shuhao; Zhou, Jingyi; Zhang, Jianmin; Shi, Ligen

doi:10.14336/ad.2021.0520

Cited by 34 publications

(19 citation statements)

References 25 publications

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“…3h). Additionally, the transcriptional signature of cluster 2 was found to be similar to a previously described subtype of microglia, Highly-Activated Microglia, which only appear in old mice 30 (Fig. 3h).…”

Section: Signature Of Senescent Microgliasupporting

confidence: 77%

TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

Rachmian

Medina

Cherqui

et al. 2023

Preprint

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Dementia in general, and Alzheimer's disease (AD) in particular, are age-related diseases (1,2). AD is associated with multiple causative factors (3,4), among which local brain inflammation plays a significant role (5). Microglia, the brain-resident immune cells, are activated along the disease course (6,7). Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor (8,9). A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

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Section: Signature Of Senescent Microgliasupporting

confidence: 77%

TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

Rachmian

Medina

Cherqui

et al. 2023

Preprint

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“…Therefore, we postulate that these antigen-presenting microglia subtypes represent highly activated reactive microglia that are strongly associated with prion disease. Cd74 is thought of as a marker of M1 microglial activation, and is expressed by highly activated microglia in the diseased-brain [ 37 , 79 ], supporting this notion.…”

Section: Resultsmentioning

confidence: 96%

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

Slota

Sajesh

Frost

et al. 2022

acta neuropathol commun

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Prion diseases are neurodegenerative disorders with long asymptomatic incubation periods, followed by a rapid progression of cognitive and functional decline culminating in death. The complexity of intercellular interactions in the brain is challenging to unravel and the basis of disease pathobiology remains poorly understood. In this study, we employed single cell RNA sequencing (scRNAseq) to produce an atlas of 147,536 single cell transcriptomes from cortex and hippocampus of mice infected with prions and showing clinical signs. We identified transcriptionally distinct populations and sub-populations of all the major brain cell-types. Disease-related transcription was highly specific to not only overarching cell-types, but also to sub-populations of glia and neurons. Most striking was an apparent decrease in relative frequency of astrocytes expressing genes that are required for brain homeostasis such as lipid synthesis, glutamate clearance, synaptic modulation and regulation of blood flow. Additionally, we described a spectrum of microglial activation states that suggest delineation of phagocytic and neuroinflammatory functions in different cell subsets. Differential responses of immature and mature neuron populations were also observed, alongside abnormal hippocampal neurogenesis. Our scRNAseq library provides a new layer of knowledge on single cell gene expression in prion disease, and is a basis for a more detailed understanding of cellular interplay that leads to neurodegeneration.

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“…In the acute phase after TBI, the upregulation of Ctss expression was mainly observed in microglia; inhibiting Ctss could reduce the level of inflammatory factors, alleviate brain edema, and improve neurobehavioral function [68]. The Cd74 molecule is the cognate receptor of macrophage migration inhibitory factor that is recognized to be a pleiotropic inflammatory cytokine [69,70]. Tobin et al [45] found that TBIinduced neurodegeneration depended on antigen processing and presentation that required Cd74.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

Zeng¹,

Zhao²,

Zhao³

et al. 2023

J. Integr. Neurosci.

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Background: Traumatic brain injury (TBI) is a common brain injury with a high morbidity and mortality. The complex injury cascade triggered by TBI can result in permanent neurological dysfunction such as cognitive impairment. In order to provide new insights for elucidating the underlying molecular mechanisms of TBI, this study systematically analyzed the transcriptome data of the rat hippocampus in the subacute phase of TBI. Methods: Two datasets (GSE111452 and GSE173975) were downloaded from the Gene Expression Omnibus (GEO) database. Systematic bioinformatics analyses were performed, including differentially expressed genes (DEGs) analysis, gene set enrichment analysis (GSEA), Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, protein-protein interaction (PPI) network construction, and hub gene identification. In addition, hematoxylin and eosin (HE), Nissl, and immunohistochemical staining were performed to assess the injured hippocampus in a TBI rat model. The hub genes identified by bioinformatics analyses were verified at the mRNA expression level. Results: A total of 56 DEGs were shared in the two datasets. GSEA results suggested significant enrichment in the MAPK and PI3K/Akt pathways, focal adhesion, and cellular senescence. GO and KEGG analyses showed that the common DEGs were predominantly related to immune and inflammatory processes, including antigen processing and presentation, leukocyte-mediated immunity, adaptive immune response, lymphocyte-mediated immunity, phagosome, lysosome, and complement and coagulation cascades. A PPI network of the common DEGs was constructed, and 15 hub genes were identified. In the shared DEGs, we identified two transcription co-factors and 15 immune-related genes. The results of GO analysis indicated that these immune-related DEGs were mainly enriched in biological processes associated with the activation of multiple cells such as microglia, astrocytes, and macrophages. HE and Nissl staining results demonstrated overt hippocampal neuronal damage. Immunohistochemical staining revealed a marked increase in the number of Iba1-positive cells in the injured hippocampus. The mRNA expression levels of the hub genes were consistent with the transcriptome data. Conclusions: This study highlighted the potential pathological processes in TBI-related hippocampal impairment. The crucial genes identified in this study may serve as novel biomarkers and therapeutic targets, accelerating the pace of developing effective treatments for TBI-related hippocampal impairment.

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A Unique Type of Highly-Activated Microglia Evoking Brain Inflammation via Mif/Cd74 Signaling Axis in Aged Mice

Cited by 34 publications

References 25 publications

TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

TREM2-dependent senescent microglia conserved in aging and Alzheimer’s disease

Dysregulation of neuroprotective astrocytes, a spectrum of microglial activation states, and altered hippocampal neurogenesis are revealed by single-cell RNA sequencing in prion disease

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

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