Microglia states and nomenclature: A field at its crossroads

Neuron, Journal Year: 2022, Volume and Issue: 110(21), P. 3458 - 3483

Published: Nov. 1, 2022

Language: Английский

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Microglia: Immune and non-immune functions

Immunity, Journal Year: 2021, Volume and Issue: 54(10), P. 2194 - 2208

Published: Oct. 1, 2021

Language: Английский

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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Language: Английский

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Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Sept. 24, 2021

Microglia are the resident macrophages of central nervous system (CNS) acting as first line defense in brain by phagocytosing harmful pathogens and cellular debris. emerge from early erythromyeloid progenitors yolk sac enter developing before establishment a fully mature blood–brain barrier. In physiological conditions, during development, microglia contribute to CNS homeostasis supporting cell proliferation neural precursors. post-natal life, such cells preserving integrity neuronal circuits sculpting synapses. After injury, change their morphology down-regulate those genes homeostatic functions. However, it is still unclear whether changes accompanied molecular functional modifications that might pathological process. While comprehensive transcriptome analyses at single-cell level have identified specific gene perturbations occurring “pathological” microglia, precise protective/detrimental role neurological disorders far being elucidated. this review, results so obtained regarding neurodegenerative will be discussed. There solid sound evidence suggesting regulating functions disease pathology represent strategy develop future therapies aimed counteracting degeneration multiple sclerosis, Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis.

Language: Английский

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ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies

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

Published: Nov. 8, 2022

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence rapidly increasing due to extended lifespans. Among number genetic risk factors identified, apolipoprotein E (APOE) gene remains strongest prevalent, impacting more than half all AD cases. While ε4 allele APOE significantly increases risk, ε2 protective relative ε3 allele. These alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function mediate lipid transport in brain periphery; however, additional functions diverse biological have been recognized. Pathogenically, seeds amyloid-β (Aβ) plaques with apoE4 driving earlier abundant amyloids. ApoE also differential effects on multiple Aβ-related or Aβ-independent pathways. complexity biology pathobiology presents challenges designing effective apoE-targeted therapeutic strategies. This review examines key pathobiological pathways related targeting strategies a specific focus latest technological advances tools.

Language: Английский

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Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(5), P. 588 - 595

Published: May 1, 2022

Abstract The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark Parkinson’s disease (PD). Nevertheless, molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed protocol to enrich and transcriptionally profile from patients PD matched controls, sampling total 387,483 nuclei, including 22,048 profiles. We identified ten populations spatially localized each SNpc using Slide-seq. A single subtype, marked by expression gene AGTR1 confined ventral tier SNpc, was highly susceptible in showed strongest upregulation targets TP53 NR2F2 , nominating processes degeneration. This same vulnerable population specifically enriched for heritable risk PD, highlighting importance cell-intrinsic determining differential PD-associated

Language: Английский

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hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data

Cell Reports Methods, Journal Year: 2023, Volume and Issue: 3(6), P. 100498 - 100498

Published: June 1, 2023

Biological systems are immensely complex, organized into a multi-scale hierarchy of functional units based on tightly regulated interactions between distinct molecules, cells, organs, and organisms. While experimental methods enable transcriptome-wide measurements across millions popular bioinformatic tools do not support systems-level analysis. Here we present hdWGCNA, comprehensive framework for analyzing co-expression networks in high-dimensional transcriptomics data such as single-cell spatial RNA sequencing (RNA-seq). hdWGCNA provides functions network inference, gene module identification, enrichment analysis, statistical tests, visualization. Beyond conventional RNA-seq, is capable performing isoform-level analysis using long-read data. We showcase from autism spectrum disorder Alzheimer's disease brain samples, identifying disease-relevant modules. directly compatible with Seurat, widely used R package demonstrate the scalability by dataset containing nearly 1 million cells.

Language: Английский

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Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease

Neuron, Journal Year: 2022, Volume and Issue: 110(11), P. 1788 - 1805.e10

Published: April 4, 2022

Language: Английский

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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(9)

Published: July 22, 2021

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation microglia. Because variants genes expressed in microglia correlate with AD risk, microglial response to plausibly impacts course. In mouse models, single-cell RNA sequencing (scRNA-seq) analyses delineated this as progressive conversion homeostatic into disease-associated (DAM); additional reactive populations have been reported other models neurodegeneration neuroinflammation. We review all these signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, proliferating propose that are either just one or a combination, depending on the clustering strategy applied model. further single-nucleus (snRNA-seq) data from human specimens discuss reasons for parallels discrepancies between transcriptional profiles. Finally, we outline future directions delineating impact pathogenesis.

Language: Английский

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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

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