Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction DOI Creative Commons
Angélica María Sabogal-Guáqueta, Alejandro Marmolejo-Garza, Marina Trombetta-Lima

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 13, 2023

Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves switch from oxidative phosphorylation (OXPHOS) glycolysis or alterations other pathways. However, most experimental findings have been acquired murine cells, and little known about human microglia. In this study, we investigate transcriptomic, proteomic, profiles mouse iPSC-derived microglia challenged with TLR4 agonist LPS. We demonstrate that both species display shift an overall increased glycolytic gene signature LPS treatment. The characterized by upregulation hexokinases phosphofructokinases study provides direct comparison metabolism between microglia, highlighting species-specific pathways involved immunometabolism importance considering these differences translational research.

Language: Английский

Human microglial state dynamics in Alzheimer’s disease progression DOI Creative Commons
Na Sun, Matheus B. Victor, Yongjin Park

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4386 - 4403.e29

Published: Sept. 1, 2023

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus transcriptomes epigenomes across 443 human subjects diverse Alzheimer's (AD) pathological phenotypes. We annotate 12 transcriptional states, including AD-dysregulated homeostatic, inflammatory, lipid-processing states. identify 1,542 AD-differentially-expressed genes, both microglia-state-specific disease-stage-specific alterations. By integrating epigenomic, transcriptomic, motif information, infer upstream regulators of cell gene-regulatory networks, enhancer-gene links, transcription-factor-driven state transitions. demonstrate that ectopic expression our predicted homeostatic-state activators induces homeostatic features in iPSC-derived microglia-like cells, while inhibiting inflammation can block inflammatory progression. Lastly, pinpoint the AD-risk genes differential their during AD Overall, provide insights underlying state-specific AD-stage-specific alterations at unprecedented resolution.

Language: Английский

Citations

174
Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function DOI Creative Commons
Alanna G. Spiteri, Claire L. Wishart, Roger Pamphlett

et al.

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 143(2), P. 179 - 224

Published: Dec. 1, 2021

Abstract In neurological diseases, the actions of microglia, resident myeloid cells CNS parenchyma, may diverge from, or intersect with, those recruited monocytes to drive immune-mediated pathology. However, defining precise roles each cell type has historically been impeded by lack discriminating markers and experimental systems capable accurately identifying them. Our ability distinguish microglia from in neuroinflammation advanced with single-cell technologies, new drugs that identify deplete them, respectively. Nevertheless, focus individual studies on particular types, diseases approaches limited our connect phenotype function more widely across diverse pathologies. Here, we critically review, tabulate integrate disease-specific functions immune profiles provide a comprehensive atlas responses viral encephalitis, demyelination, neurodegeneration ischemic injury. emphasizing differential severe neuroinflammatory disease inflammatory pathways common equally incapacitating less inflammation. We examine these findings context human highlight benefits inherent limitations animal models impede facilitate clinical translation. This enables us contrasting, non-redundant often opposing could be targeted therapeutically.

Language: Английский

Citations

148
The effects of microglia-associated neuroinflammation on Alzheimer’s disease DOI Creative Commons
Cuicui Wang, Shuai Zong, Xiaolin Cui

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Feb. 22, 2023

Alzheimer’s disease (AD) is defined as a severe chronic degenerative neurological in human. The pathogenic mechanism of AD has been convincingly elucidated by the “amyloid cascade hypothesis” with main focus pathological accretion β-amyloid (Aβ) peptides outside cell. However, increasing evidence suggests that this hypothesis weak explaining pathogenesis AD. Neuroinflammation crucial development AD, which proven elevated levels inflammatory markers and identification risk genes relevant to innate immune function. Here, we summarize effects microglia-mediated neuroinflammation on focusing temporal spatial changes microglial phenotype, interactions among microglia, Aβ, tau, neurons, prospects recent advances diagnostic therapeutic target

Language: Английский

Citations

140
Diverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology DOI Creative Commons
Amy M. Smith, Kenneth Davey, Stergios Tsartsalis

et al.

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 143(1), P. 75 - 91

Published: Nov. 12, 2021

To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes astrocyte nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD control brains with a range of amyloid-beta phospho-tau (pTau) pathology. Significant differences glial gene expression (including risk genes expressed both the [CLU, MEF2C, IQCK] [APOE, MS4A6A, PILRA]) were correlated tissue amyloid or pTau expression. The differentially distinct between two cell types pathologies, although common (but cell-type specific) sets pathologies each type. Astrocytes showed enrichment for proteostatic, inflammatory metal ion homeostasis pathways. Pathways phagocytosis, inflammation proteostasis perivascular macrophages greater amyloid, but IL1-related pathway was found specifically association pTau. We also distinguishable sub-clusters characterised by transcriptional signatures related either homeostatic functions Gene co-expression analyses revealed potential functional associations soluble biomarkers (CLU) (GPNMB). Our work highlights responses pathological protein clearance inflammation, as well diversity AD.

Language: Английский

Citations

132
Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria DOI
Prashanth Gowda, P. Hemachandra Reddy, Subodh Kumar

et al.

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 73, P. 101529 - 101529

Published: Nov. 20, 2021

Language: Английский

Citations

107
Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence DOI
Insup Choi, Minghui Wang, Seungyeul Yoo

et al.

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(7), P. 963 - 974

Published: May 25, 2023

Language: Английский

Citations

105
Early Alzheimer’s disease pathology in human cortex involves transient cell states DOI Creative Commons
Vahid Gazestani, Tushar Kamath, Naeem Nadaf

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4438 - 4453.e23

Published: Sept. 1, 2023

Language: Английский

Citations

103
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

100
Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease DOI Creative Commons
Yun Li, Xiaohuan Xia, Yi Wang

et al.

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

Published: Oct. 6, 2022

Abstract Alzheimer's disease (AD) is the most common neurodegenerative in elderly globally. Emerging evidence has demonstrated microglia-driven neuroinflammation as a key contributor to onset and progression of AD, however, mechanisms that mediate remain largely unknown. Recent studies have suggested mitochondrial dysfunction including DNA (mtDNA) damage, metabolic defects, quality control (QC) disorders precedes microglial activation subsequent neuroinflammation. Therefore, an in-depth understanding relationship between AD important unveil pathogenesis develop effective approaches for early diagnosis treatment. In this review, we summarized current progress roles mtDNA, metabolism, QC changes provide comprehensive thoughts targeting mitochondria potential therapeutic strategies AD.

Language: Английский

Citations

83
Human microglia show unique transcriptional changes in Alzheimer’s disease DOI Creative Commons
Katherine E. Prater,

Kevin J. Green,

Sainath Mamde

et al.

Nature Aging, Journal Year: 2023, Volume and Issue: 3(7), P. 894 - 907

Published: May 29, 2023

Abstract Microglia, the innate immune cells of brain, influence Alzheimer’s disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, regulation which is not fully understood, complicating therapeutics development. To better define transcriptomic phenotypes gene regulatory networks associated with AD, we enriched for nuclei from 12 AD 10 control human dorsolateral prefrontal cortices (7 males 15 females, all aged >60 years) before single-nucleus RNA sequencing. Here describe both established previously unrecognized microglial molecular phenotypes, inferred driving observed change, apply trajectory analysis to reveal putative relationships between phenotypes. We identify more prevalent in cases compared controls. Further, heterogeneity subclusters expressing homeostatic markers. Our study demonstrates that deep profiling brain can provide insight into transcriptional changes AD.

Language: Английский

Citations

80