Transcriptional landscape of human microglia implicates age, sex, and APOE ‐related immunometabolic pathway perturbations DOI Creative Commons
Tulsi Patel, Troy Carnwath, Xue Wang

et al.

Aging Cell, Journal Year: 2022, Volume and Issue: 21(5)

Published: April 6, 2022

Abstract Microglia have fundamental roles in health and disease; however, effects of age, sex, genetic factors on human microglia not been fully explored. We applied bulk single‐cell approaches to comprehensively characterize transcriptomes their associations with APOE . identified a novel microglial signature, characterized its expression tissue transcriptomes. discovered co‐expression network modules associated ‐ε4 that are enriched for lipid carbohydrate metabolism genes. Integrated analyses revealed significant overlap between age‐associated module genes both pro‐inflammatory disease‐associated clusters. These clusters harbor known neurodegenerative disease including , PLCG2 BIN1 Meta‐analyses published datasets further supported our findings. Thus, these data represent well‐characterized transcriptome resource highlight ‐related immunometabolism perturbations potential relevance neurodegeneration.

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 reprogram metabolic profiles for phenotype and function changes in central nervous system DOI Creative Commons
Sheng Yang, Chuan Qin,

Zi-Wei Hu

et al.

Neurobiology of Disease, Journal Year: 2021, Volume and Issue: 152, P. 105290 - 105290

Published: Feb. 6, 2021

In response to various types of environmental and cellular stress, microglia rapidly activate exhibit either pro- or anti-inflammatory phenotypes maintain tissue homeostasis. Activation can result in changes morphology, phagocytosis capacity, secretion cytokines. Furthermore, microglial activation also induces energy demand, which is dependent on the metabolism metabolic substrates including glucose, fatty acids, amino acids. Accumulating evidence demonstrates reprogramming acts as a key driver immune response. For instance, pro-inflammatory states preferentially use glycolysis for production, whereas, cells are mainly powered by oxidative phosphorylation acid oxidation. this review, we summarize recent findings regarding pathways under physiological pathological circumtances. We will then discuss how orchestrate variety central nervous system pathologies. Finally, highlight manipulating reprogram towards beneficial functions, illustrate therapeutic potential inflammation-related neurological diseases.

Language: Английский

Citations

142
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
Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration DOI
Oliver Kann,

Fadi Almouhanna,

Bruno Chausse

et al.

Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 45(12), P. 913 - 927

Published: Oct. 22, 2022

Language: Английский

Citations

72
Metabolic reprogramming and polarization of microglia in Parkinson’s disease: Role of inflammasome and iron DOI
Haiyang Yu, Qing Chang,

Tong Sun

et al.

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 90, P. 102032 - 102032

Published: Aug. 10, 2023

Language: Английский

Citations

61
Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation DOI Creative Commons
Mengran Zhang, Huaqing Chen, Wenlong Zhang

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 10(12)

Published: Feb. 17, 2023

Abstract Neuroinflammation, for which microglia are the predominant contributors, is a significant risk factor cognitive dysfunction. Riboflavin (also known as vitamin B2) ameliorates impairment via anti‐oxidative stress and anti‐inflammation properties; however, underlying mechanisms linking riboflavin metabolism microglial function in remain unclear. Here, it demonstrated that kinase (RFK), critical enzyme metabolism, specifically expressed microglia. An intermediate product of riboflavin, flavin mononucleotide (FMN), inhibited RFK expression regulation lysine‐specific methyltransferase 2B (KMT2B). FMN supplementation attenuated pro‐inflammatory TNFR1/NF‐ κ B signaling pathway, this effect abolished by KMT2B overexpression. To improve limited anti‐inflammatory efficiency free FMN, biomimetic nanoparticle strategy (designated MNPs@FMN) established, penetrated blood brain barrier with enhanced microglial‐targeted delivery efficiency. Notably, MNPs@FMN ameliorated dysfunctional synaptic plasticity lipopolysaccharide‐induced inflammatory mouse model 5xFAD Alzheimer's disease. Taken together, may serve potential therapeutic approach inflammation‐dependent decline.

Language: Английский

Citations

50
Emerging role of senescent microglia in brain aging-related neurodegenerative diseases DOI Creative Commons
Chan Rim, Min-Jung You, Minyeop Nahm

et al.

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Feb. 20, 2024

Abstract Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain pathogenesis of these conditions remains inadequately understood. Cellular senescence considered to contribute cellular dysfunction inflammaging. According threshold theory senescent cell accumulation, vulnerability associated with rates generation clearance within brain. Given role microglia in eliminating cells, accumulation may lead acceleration aging, contributing inflammaging increased diseases. In this review, we propose idea that microglia, which notably vulnerable could potentially serve as central catalyst progression The are emerging promising target mitigating

Language: Английский

Citations

36
Brain energy metabolism: A roadmap for future research DOI Creative Commons
Caroline Rae, Joseph A. Baur, Karin Borges

et al.

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 168(5), P. 910 - 954

Published: Jan. 6, 2024

Although we have learned much about how the brain fuels its functions over last decades, there remains still to discover in an organ that is so complex. This article lays out major gaps our knowledge of interrelationships between metabolism and function, including biochemical, cellular, subcellular aspects functional imaging adult brain, as well during development, aging, disease. The focus on unknowns substrates associated transporters, roles insulin lipid droplets, emerging role microglia, mysteries cofactor signaling molecule NAD

Language: Английский

Citations

33
Phagocytic astrocytes: Emerging from the shadows of microglia DOI Creative Commons
Hiroyuki Konishi, Schuichi Koizumi, Hiroshi Kiyama

et al.

Glia, Journal Year: 2022, Volume and Issue: 70(6), P. 1009 - 1026

Published: Feb. 10, 2022

Abstract Elimination of dead or live cells take place in both a healthy and diseased central nervous system (CNS). Dying are quickly cleared by phagocytosis for the maintenance CNS recovery after injury. Live parts thereof, such as synapses myelin, appropriately eliminated to maintain refine neural networks during development adulthood. Microglia, specific population resident macrophages CNS, classically considered primary phagocytes; however, astrocytes have also been highlighted phagocytes last decade. Phagocytic targets receptors reported be mostly common between microglia, which raises question how astrocytic differs from microglial phagocytosis, these two phagocytic systems cooperate. In this review, we address consequences particularly focusing on elusive points.

Language: Английский

Citations

63
Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders DOI Creative Commons
Gang Luo, Xiaofeng Wang, Yongchen Cui

et al.

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: Nov. 13, 2021

Microglial polarization toward pro-inflammatory M1 phenotype are major contributors to the development of perioperative neurocognitive disorders (PNDs). Metabolic reprogramming plays an important role in regulating microglial polarization. We therefore hypothesized that surgical trauma can activate by metabolic induce hippocampal neuroinflammation and subsequent postoperative cognitive impairment.We used aged mice establish a model PNDs, investigated whether induced reprograming hippocampus using PET/CT GC/TOF-MS based metabolomic analysis. then determined effect glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on polarization, neuroinflammation, function at 3 d after surgery.We found surgery group had less context-related freezing time than either control or anesthesia (P < 0.05) without significant difference tone-related > 0.05). The level Iba-1 fluorescence intensity were significantly increased accompanied activated morphological changes microglia expression iNOS/CD86 (M1 marker) enriched from metabolomics analysis indicated provoked oxidative phosphorylation glycolysis hippocampus. Inhibition 2-DG alleviated increase (CD86+CD206-) up-regulation mediators (IL-1β IL-6) Furthermore, inhibition ameliorated dependent deficit caused trauma.Metabolic is crucial for PNDs. Manipulating metabolism might provide valuable therapeutic strategy treating

Language: Английский

Citations

59