Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response DOI Creative Commons
Anna A. Pimenova,

Manon Herbinet,

Ishaan Gupta

et al.

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 148, P. 105217 - 105217

Published: Dec. 8, 2020

More than forty loci contribute to genetic risk for Alzheimer's disease (AD). These alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, AD risk. We have previously identified SPI1/PU.1, a master regulator of development brain and periphery, as factor AD. Higher expression SPI1 is associated with increased AD, while lower protective. To investigate molecular cellular phenotypes higher PU.1 we used stable overexpression knock-down BV2, an immortalized mouse microglial line. Transcriptome analysis suggests reduced suppresses homeostatic genes similar disease-associated microglia response amyloid plaques models Moreover, resulted activation protein translation, antioxidant action cholesterol/lipid metabolism pathways concomitant decrease pro-inflammatory gene expression. upregulated downregulated phagocytic uptake BV2 cells independent nature engulfed material. However, retained their ability internalize myelin control albeit delay, which aligns anti-inflammatory profile. Here several responses modulated by levels propose association driven due viability under cytotoxic conditions. In contrast, low leads death conditions accompanied signaling decreased A1 reactive astrocytes signature supporting protective effect genotype findings inform future vivo validation studies design small molecule screens therapeutic discovery

Language: Английский

Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential DOI
Kazuhide Inoue, Makoto Tsuda

Nature reviews. Neuroscience, Journal Year: 2018, Volume and Issue: 19(3), P. 138 - 152

Published: Feb. 8, 2018

Language: Английский

Citations

692
A human cell atlas of fetal gene expression DOI
Junyue Cao,

Diana R. O’Day,

Hannah A. Pliner

et al.

Science, Journal Year: 2020, Volume and Issue: 370(6518)

Published: Nov. 12, 2020

The genomics of human development Understanding the trajectory a developing requires an understanding how genes are regulated and expressed. Two papers now present pooled approach using three levels combinatorial indexing to examine single-cell gene expression chromatin landscapes from 15 organs in fetal samples. Cao et al. focus on measurements RNA broadly distributed cell types provide insights into organ specificity. Domcke examined accessibility cells these identify regulatory elements that regulate expression. Together, analyses generate comprehensive atlases early development. Science , this issue p. eaba7721 eaba7612

Language: Английский

Citations

614
Microglia and early brain development: An intimate journey DOI
Morgane Sonia Thion, Florent Ginhoux, Sonia Garel

et al.

Science, Journal Year: 2018, Volume and Issue: 362(6411), P. 185 - 189

Published: Oct. 11, 2018

Cross-talk between the nervous and immune systems has been well described in context of adult physiology disease. Recent advances our understanding cell ontogeny have revealed a notable interplay neurons microglia during prenatal postnatal emergence functional circuits. This Review focuses on brain, where early symbiotic relationship neuronal cells critically regulates wiring, contributes to sex-specific differences neural circuits, relays crucial information from periphery, including signals derived microbiota. These observations underscore importance studying neurodevelopment as part broader framework that considers system interactions with whole-body context.

Language: Английский

Citations

348
Niche-Specific Reprogramming of Epigenetic Landscapes Drives Myeloid Cell Diversity in Nonalcoholic Steatohepatitis DOI Creative Commons
Jason S. Seidman, Ty D. Troutman, Mashito Sakai

et al.

Immunity, Journal Year: 2020, Volume and Issue: 52(6), P. 1057 - 1074.e7

Published: May 1, 2020

Language: Английский

Citations

326
Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities DOI Creative Commons
Anne-Laure Hemonnot-Girard, Jennifer Hua, Lauriane Ulmann

et al.

Frontiers in Aging Neuroscience, Journal Year: 2019, Volume and Issue: 11

Published: Aug. 30, 2019

Microglia are the resident macrophages of central nervous system. They play key roles in brain development and physiology during life aging. Equipped with a variety molecular sensors through various functions they can fulfil, critically involved maintaining brain's homeostasis. In Alzheimer disease (AD), microglia reaction was initially thought to be incidental triggered by amyloid deposits dystrophic neurites. However, recent genome-wide association studies have established that majority AD risk loci found or near genes highly sometimes uniquely expressed microglia. This leads concept being early steps identified them as important potential therapeutic targets. Whether is beneficial, detrimental both progression still unclear subject intense debate. this review, we presenting state-of-knowledge report intended highlight microglial pathways shown progression. We first address acquisition new alteration their homeostatic reactive Second, propose summary parameters currently emerging field need considered identify relevant Finally, discuss many obstacles designing efficient strategies for present innovative technologies may foster our understanding pathology. Ultimately, work aims fly over make general reliable current knowledge regarding microglia's involvement research opportunities field.

Language: Английский

Citations

289
Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition DOI Creative Commons
Emanuela Pasciuto, Oliver T. Burton, Carlos P. Roca

et al.

Cell, Journal Year: 2020, Volume and Issue: 182(3), P. 625 - 640.e24

Published: July 22, 2020

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence healthy remains controversial, and function largely unknown. We used combination imaging, single cell, surgical approaches to identify CD69+ cell population both mouse human brain, distinct from circulating cells. brain-resident was derived through situ differentiation activated circulatory shaped by self-antigen peripheral microbiome. Single-cell sequencing revealed that absence murine cells, resident microglia remained suspended between fetal adult states. This maturation defect resulted excess immature neuronal synapses behavioral abnormalities. These results illuminate role for development potential interconnected dynamic evolution immunological neurological systems. VIDEO ABSTRACT.

Language: Английский

Citations

269
Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer’s disease DOI Creative Commons
Akira Sobue, Okiru Komine, Yuichiro Hara

et al.

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: Jan. 5, 2021

Abstract Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia aging and neurodegenerative model mice show a loss homeostatic phenotype activation disease-associated (DAM), correlation between those phenotypes degree neuronal cell not clarified. In this study, we performed RNA sequencing isolated from three representative mouse models, App NL - G F/NL F with amyloid pathology, rTg4510 tauopathy, SOD1 G93A motor neuron by magnetic activated sorting. parallel, gene expression patterns human precuneus early change (n = 11) control brain 14) were also analyzed sequencing. We found that substantial reduction microglial genes microglia, whereas DAM uniformly upregulated all models. The was correlated loss. AD reduced related to microglia- oligodendrocyte-specific markers observed, although upregulated. Our results implicate function progression other diseases. Moreover, analyses suggest oligodendrocyte functions induced pathology human.

Language: Английский

Citations

193
Progress in brain cannabinoid CB2 receptor research: From genes to behavior DOI
Chloe J. Jordan, Zheng‐Xiong Xi

Neuroscience & Biobehavioral Reviews, Journal Year: 2019, Volume and Issue: 98, P. 208 - 220

Published: Jan. 3, 2019

Language: Английский

Citations

167
Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity DOI Creative Commons
Simone Bido, Sharon Muggeo, Luca Massimino

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Oct. 29, 2021

Abstract Recent findings in human samples and animal models support the involvement of inflammation development Parkinson’s disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event neurodegeneration. We generated new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation cells. Surprisingly, these mice developed progressive degeneration dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics functional assessment revealed that αSYN-accumulating cells strong reactive state with phagocytic exhaustion excessive production oxidative proinflammatory molecules. This inflammatory created molecular feed-forward vicious cycle between microglia IFNγ-secreting immune infiltrating brain parenchyma. Pharmacological inhibition nitrosative molecule was sufficient to attenuate These results suggest induces DA neuronal promoting exhaustion, an excessively toxic environment recruitment peripheral

Language: Английский

Citations

119
Transcriptional Alterations in Dorsolateral Prefrontal Cortex and Nucleus Accumbens Implicate Neuroinflammation and Synaptic Remodeling in Opioid Use Disorder DOI Creative Commons
Marianne L. Seney,

Sam-Moon Kim,

Jill R. Glausier

et al.

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 90(8), P. 550 - 562

Published: June 12, 2021

BackgroundPrevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge overdose deaths. While dependence has been extensively studied in preclinical models, an understanding the biological alterations that occur brains people who chronically opioids and are diagnosed with OUD remains limited. To address this limitation, RNA sequencing was conducted on dorsolateral prefrontal cortex nucleus accumbens, regions heavily implicated OUD, from postmortem subjects OUD.MethodsWe performed accumbens unaffected comparison (n = 20) 20). Our transcriptomic analyses identified differentially expressed transcripts investigated transcriptional coherence between brain using rank-rank hypergeometric orderlap. Weighted gene coexpression OUD-specific modules networks. Integrative genome-wide association study datasets linkage disequilibrium scores assessed genetic liability psychiatric-related phenotypes OUD.ResultsRank-rank overlap revealed extensive related to synaptic remodeling neuroinflammation. Identified were enriched for factors control proinflammatory cytokine, chondroitin sulfate, extracellular matrix signaling. Cell-type deconvolution role microglia as potential driver opioid-induced neuroplasticity. Linkage score analysis suggested liabilities risky behavior, attention-deficit/hyperactivity disorder, depression OUD.ConclusionsOverall, our findings suggest connections brain's immune system human brain.

Language: Английский

Citations

113