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

Single-cell RNA sequencing reveals time- and sex-specific responses of mouse spinal cord microglia to peripheral nerve injury and links ApoE to chronic pain DOI Creative Commons
Shannon Tansley,

Sonali Uttam,

Alba Ureña Guzmán

et al.

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

Published: Feb. 11, 2022

Abstract Activation of microglia in the spinal cord following peripheral nerve injury is critical for development long-lasting pain hypersensitivity. However, it remains unclear whether distinct subpopulations or states contribute to different stages and maintenance. Using single-cell RNA-sequencing, we show that induces generation a male-specific inflammatory subtype, demonstrate increased proliferation male as compared female mice. We also time- sex-specific transcriptional changes microglial injury. Apolipoprotein E ( Apoe ) top upregulated gene at chronic time points after Furthermore, polymorphisms APOE humans are associated with pain. Single-cell RNA sequencing analysis human reveals subpopulation disease-related signature. Our data provide detailed mouse microglia, identify link between ApoE humans.

Language: Английский

Citations

111
Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer’s disease DOI Creative Commons
Mengmeng Jin, Ranjie Xu, Le Wang

et al.

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(7), P. 1135 - 1153.e8

Published: July 1, 2022

Language: Английский

Citations

95
TREM2 dependent and independent functions of microglia in Alzheimer’s disease DOI Creative Commons
Jinchao Hou, Yun Chen,

Gary E. Grajales‐Reyes

et al.

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Dec. 23, 2022

Abstract Microglia are central players in brain innate immunity and have been the subject of extensive research Alzheimer’s disease (AD). In this review, we aim to summarize genetic functional discoveries that advanced our understanding microglia reactivity AD pathology. Given heightened risk posed by rare variants microglial triggering receptor expressed on myeloid cells 2 (TREM2), will focus studies addressing impact responses amyloid plaques, tauopathy demyelination pathologies mouse human. Finally, discuss implications recent TREM2 biology potential therapeutic strategies for AD.

Language: Английский

Citations

92
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

78
Neuroinflammation in Alzheimer’s disease: microglial signature and their relevance to disease DOI Creative Commons
Akira Sobue, Okiru Komine, Koji Yamanaka

et al.

Inflammation and Regeneration, Journal Year: 2023, Volume and Issue: 43(1)

Published: May 10, 2023

Alzheimer's disease (AD) is the most common form of dementia, pathologically characterized by senile plaques and neurofibrillary tangles (NFTs), resulting in neurodegeneration. Neuroinflammation, defined as activation glial cells such microglia astrocytes, observed surrounding affected neurons AD. Recently conducted genome-wide association studies (GWAS) indicate that a large section identified AD risk genes are involved immune responses enriched microglia. Microglia innate central nervous system (CNS), which surveillance maintenance homeostasis CNS. Recently, novel subpopulation activated named disease-associated (DAM), also known response (ARM) or microglial neurodegenerative phenotype (MGnD), was model mice. These closely associate with β-amyloid (Aβ) exhibit characteristic gene expression profiles accompanied reduced expressions homeostatic genes. However, it remains unclear whether decreased functions increased DAM/ARM/MGnD correlate degree neuronal loss To translate results rodent to human AD, precuneus, brain region vulnerable accumulation preclinical high interest, can provide insights into mechanisms Aβ early In this study, we performed comparative analyses among three representative mouse models precunei pathology. We proceeded evaluate potential therapeutic targets for believe our findings will important resources better understand role dysfunction

Language: Английский

Citations

61
Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements DOI Creative Commons
Ashlyn G. Anderson, Brianne B. Rogers, Jacob M. Loupe

et al.

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(3), P. 100263 - 100263

Published: Feb. 2, 2023

Cell type-specific transcriptional differences between brain tissues from donors with Alzheimer's disease (AD) and unaffected controls have been well documented, but few studies rigorously interrogated the regulatory mechanisms responsible for these alterations. We performed single nucleus multiomics (snRNA-seq plus snATAC-seq) on 105,332 nuclei isolated cortical 7 AD 8 to identify candidate

Language: Английский

Citations

49
Epigenetics Control Microglia Plasticity DOI Creative Commons
Mathilde Cheray, Bertrand Joseph

Frontiers in Cellular Neuroscience, Journal Year: 2018, Volume and Issue: 12

Published: Aug. 3, 2018

Microglia, resident immune cells of the central nervous system, fulfil multiple functions in brain throughout life. These microglial range from participation innate and adaptive responses, involvement development its homeostasis maintenance, to contribution degenerative, traumatic proliferative diseases; take place developing, aging, healthy, or diseased brain. Thus, an impressive level cellular plasticity, appears as a requirement for pleiotropic biological microglia. Epigenetic changes, including histone modifications DNA methylation well microRNA expression, are important modifiers gene have been involved cell phenotype regulation reprogramming therefore part mechanisms regulating plasticity. Here, we review discuss epigenetic mechanisms, which emerging contributors this plasticity thereby can constitute interesting targets modulate microglia associated diseases, developmental neurodegenerative diseases cancer.

Language: Английский

Citations

120
Microglial TLR4-dependent autophagy induces ischemic white matter damage via STAT1/6 pathway DOI Creative Commons
Chuan Qin, Qian Liu,

Zi-Wei Hu

et al.

Theranostics, Journal Year: 2018, Volume and Issue: 8(19), P. 5434 - 5451

Published: Jan. 1, 2018

Rationale: Ischemic white matter damage frequently results in myelin loss, accompanied with microglial activation.We previously found that directing microglia towards an anti-inflammatory phenotype provided a beneficial microenvironment and helped maintain integrity during chronic cerebral hypoperfusion.However, the molecular mechanisms underlying polarization remain elusive.Methods: Hypoperfusion induced mice model lipopolysaccharide (LPS) primary cultured were established.Autophagy activation was detected both vivo vitro by immunofluorescence, Western blot electron microscopy.Autophagy inhibitors/agonist administrated to investigate role of autophagic process modulating phenotypes.Quantitative real time-polymerase chain reaction carried out possible pathway.Results: We identified rapid accumulation autophagosomes exposed LPS within activated ischemic damage.Autophagy inhibitors switched function from pro-inflammatory phenotype.Furthermore, we TLR4, one major receptors binding LPS, most highly expressed on corpus callosum damage, TLR4 deficiency could mimic phenomenon functional transformation, exhibit protective activity hypoperfusion.Whereas, group largely abolished process.Finally, our transcriptional analysis confirmed up-regulation STAT1 down-regulation STAT6 exposure be reversed autophagy inhibition.Conclusion: These indicated TLR4-dependent regulates induces via STAT1/6 pathway.

Language: Английский

Citations

94
Microglia: Brain cells on the move DOI
Sophie Smolders, Sofie Kessels, Tim Vangansewinkel

et al.

Progress in Neurobiology, Journal Year: 2019, Volume and Issue: 178, P. 101612 - 101612

Published: April 4, 2019

Language: Английский

Citations

93
ApoE4-Induced Cholesterol Dysregulation and Its Brain Cell Type-Specific Implications in the Pathogenesis of Alzheimer's Disease. DOI
Woojin Jeong, Hyein Lee, Sukhee Cho

et al.

PubMed, Journal Year: 2019, Volume and Issue: 42(11), P. 739 - 746

Published: Nov. 30, 2019

Significant knowledge about the pathophysiology of Alzheimer's disease (AD) has been gained in last century; however, understanding its causes onset remains limited. Late-onset AD is observed 95% patients, and

Language: Английский

Citations

89