Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Сен. 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.

Язык: Английский

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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 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

Язык: Английский

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Gut microbiota-derived metabolites mediate the neuroprotective effect of melatonin in cognitive impairment induced by sleep deprivation

Microbiome, Год журнала: 2023, Номер 11(1)

Опубликована: Янв. 31, 2023

Abstract Background Sleep loss is a serious global health concern. Consequences include memory deficits and gastrointestinal dysfunction. Our previous research showed that melatonin can effectively improve cognitive impairment intestinal microbiota disturbances caused by sleep deprivation (SD). The present study further explored the mechanism which exogenous prevents SD-induced impairments. Here, we established fecal transplantation, Aeromonas colonization LPS or butyrate supplementation tests to evaluate role of its metabolites in alleviating impairment. Results Transplantation SD-gut into normal mice induced microglia overactivation neuronal apoptosis hippocampus, decline, colonic disorder, manifesting as increased levels decreased Lachnospiraceae_NK4A136 butyrate. All these events were reversed with transplantation SD + melatonin-gut microbiota. Colonization addition produced an inflammatory response hippocampus spatial mice. These changes melatonin, accompanied LPS. Butyrate administration sleep-deprived restored responses In vitro, BV2 cells, was improved supplementation. This ameliorative effect blocked pretreatment MCT1 inhibitor HDAC3 agonist but mimicked TLR4 p-P65 antagonists. Conclusions Gut microbes their mediate effects on A feasible downregulates constituent upregulates colon. lessen through crosstalk between TLR4/NF-κB MCT1/ signaling pathways.

Язык: Английский

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The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association

Stroke, Год журнала: 2023, Номер 54(6)

Опубликована: Апрель 3, 2023

Preservation of brain health has emerged as a leading public priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among cells, meninges, and hematic lymphatic vasculature (the neurovasculome) that is highly relevant to maintenance cognitive function. In this scientific statement, multidisciplinary team experts examines these advances, assesses their relevance disease, identifies knowledge gaps, provides future directions.

Язык: Английский

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Neuroinflammation, memory, and depression: new approaches to hippocampal neurogenesis

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Ноя. 27, 2023

As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks premature death other medical conditions for patients. Neuroinflammation is abnormal immune response in brain, its correlation with MDD receiving increasing attention. has been reported to be involved through distinct neurobiological mechanisms, among which dysregulation neurogenesis dentate gyrus (DG) hippocampus (HPC) The DG two niches adult mammalian neurotrophic factors are fundamental regulators this process. cell types mediating neuroinflammation include microglia, astrocytes, oligodendrocytes, meningeal leukocytes, peripheral cells selectively penetrate blood-brain barrier infiltrate into inflammatory regions. This review summarizes functions affected by during progression corresponding influences on memory patients model animals.

Язык: Английский

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The mechanism of microglia-mediated immune inflammation in ischemic stroke and the role of natural botanical components in regulating microglia: A review

Frontiers in Immunology, Год журнала: 2023, Номер 13

Опубликована: Фев. 2, 2023

Ischemic stroke (IS) is one of the most fatal diseases. Neuroimmunity, inflammation, and oxidative stress play important roles in various complex mechanisms IS. In particular, early proinflammatory response resulting from overactivation resident microglia infiltration circulating monocytes macrophages brain after cerebral ischemia leads to secondary injury. Microglia are innate immune cells that constantly monitor microenvironment under normal conditions. Once occurs, activated produce dual effects neurotoxicity neuroprotection, balance two determines fate damaged neurons. The activation defined as classical (M1 type) or alternative (M2 type). M1 type secrete pro-inflammatory cytokines neurotoxic mediators exacerbate neuronal damage, while M2 promote a repairing anti-inflammatory response. Fine regulation M1/M2 microglial minimize damage maximize protection has therapeutic value. This review focuses on interaction between other involved IS phenotypic characteristics, mechanism natural plant components regulating IS, providing novel candidate drugs for drug development.

Язык: Английский

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Transcriptional and epigenetic decoding of the microglial aging process

Nature Aging, Год журнала: 2023, Номер 3(10), С. 1288 - 1311

Опубликована: Сен. 11, 2023

Abstract As important immune cells, microglia undergo a series of alterations during aging that increase the susceptibility to brain dysfunctions. However, longitudinal characteristics remain poorly understood. In this study, we mapped transcriptional and epigenetic profiles from 3- 24-month-old mice. We first discovered unexpected sex differences identified age-dependent (ADEM) genes process. then compared features reactivity in female at single-cell resolution level. To dissect functions aged excluding influence other established an accelerated microglial turnover model without directly affecting cells. By model, achieved aged-like non-aged brains confirmed per se contribute cognitive decline. Collectively, our work provides comprehensive resource for decoding process microglia, shedding light on how maintain functions.

Язык: Английский

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Microglia regulation of central nervous system myelin health and regeneration

Nature reviews. Immunology, Год журнала: 2023, Номер 24(1), С. 49 - 63

Опубликована: Июль 14, 2023

Язык: Английский

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HMGB1 mediates synaptic loss and cognitive impairment in an animal model of sepsis-associated encephalopathy

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Март 11, 2023

Microglial activation-mediated neuroinflammation is one of the essential pathogenic mechanisms sepsis-associated encephalopathy (SAE). Mounting evidence suggests that high mobility group box-1 protein (HMGB1) plays a pivotal role in and SAE, yet mechanism by which HMGB1 induces cognitive impairment SAE remains unclear. Therefore, this study aimed to investigate underlying SAE.An model was established cecal ligation puncture (CLP); animals sham underwent cecum exposure alone without perforation. Mice inflachromene (ICM) were continuously injected with ICM intraperitoneally at daily dose 10 mg/kg for 9 days starting 1 h before CLP operation. The open field, novel object recognition, Y maze tests performed on 14-18 after surgery assess locomotor activity function. secretion, state microglia, neuronal measured immunofluorescence. Golgi staining detect changes morphology dendritic spine density. In vitro electrophysiology long-term potentiation (LTP) CA1 hippocampus. vivo neural oscillation hippocampus.CLP-induced accompanied increased secretion microglial activation. phagocytic capacity microglia enhanced, resulting aberrant pruning excitatory synapses loss reduced activity, impaired LTP, decreased theta Inhibiting treatment reversed these changes.HMGB1 activation, synaptic pruning, neuron dysfunction an animal leading impairment. These results suggest might be target treatment.

Язык: Английский

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A richer and more diverse future for microglia phenotypes

Heliyon, Год журнала: 2023, Номер 9(4), С. e14713 - e14713

Опубликована: Март 21, 2023

Microglia are the only resident innate immune cells derived from mesoderm in nerve tissue. They play a role development and maturation of central nervous system (CNS). mediate repair CNS injury participate endogenous response induced by various diseases exerting neuroprotective or neurotoxic effects. Traditionally, microglia considered to be resting state, M0 type, under physiological conditions. In this they perform surveillance constantly monitoring pathological responses CNS. undergo series morphological functional changes state eventually polarize into classically activated (M1) alternatively (M2). M1 release inflammatory factors toxic substances inhibit pathogens, while M2 exert effects promoting regeneration. However, recent years, view regarding M1/M2 polarization has gradually changed. According some researchers, phenomenon is not yet confirmed. The term used for simplified description its phenotype function. Other researchers believe that process rich diverse, consequently, classification method limitations. This conflict hinders academic community establishing more meaningful pathways terms, therefore, careful revision concept required. present article briefly reviews current consensus controversy microglial typing provide supporting materials objective understanding microglia.

Язык: Английский

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