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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Western diet as a trigger of Alzheimer’s disease: From metabolic syndrome and systemic inflammation to neuroinflammation and neurodegeneration

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 70, P. 101397 - 101397

Published: June 30, 2021

An excess of saturated fatty acids and simple sugars in the diet is a known environmental risk factor Alzheimer's disease (AD) but holistic view interacting processes through which such may contribute to AD pathogenesis missing. We addressed this need extensive analysis published studies investigating effects western (WD) on development humans laboratory animals. reviewed WD-induced systemic alterations comprising metabolic changes, induction obesity adipose tissue inflammation, gut microbiota dysbiosis acceleration low-grade inflammation. Next we provide an overview evidence demonstrating that WD-associated drive impairment blood-brain barrier (BBB) neuroinflammation paralleled by accumulation toxic amyloid. Later these changes are followed dysfunction synaptic transmission, neurodegeneration finally memory cognitive impairment. conclude WD can trigger inflammaging, BBB induced inflammation play central role process. Moreover, concurrence Aβ dyshomeostasis, reciprocal interactions vicious cycle neurodegeneration, contradicts as primary AD. Given 2019 World Health Organization recommended focusing modifiable factors prevention, sequential, complex pathomechanisms initiated WD, lead from peripheral disturbances support future prevention strategies.

Language: Английский

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Immunometabolism in the Brain: How Metabolism Shapes Microglial Function

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(11), P. 854 - 869

Published: Sept. 18, 2020

Language: Английский

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Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system

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

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Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson's disease model

Neuropharmacology, Journal Year: 2022, Volume and Issue: 207, P. 108963 - 108963

Published: Jan. 19, 2022

Language: Английский

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Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease

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

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Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(12), P. 1756 - 1774

Published: Dec. 19, 2022

Microglia continuously survey the brain parenchyma and actively shift status following stimulation. These processes demand a unique bioenergetic programme; however, little is known about metabolic determinants in microglia. By mining large datasets generating transgenic tools, here we show that hexokinase 2 (HK2), most active isozyme associated with mitochondrial membrane, selectively expressed microglia brain. Genetic ablation of HK2 reduced microglial glycolytic flux energy production, suppressed repopulation, attenuated surveillance damage-triggered migration male mice. elevation prominent immune-challenged or disease-associated In ischaemic stroke models, deletion promoted neuroinflammation potentiated cerebral damages. The enhanced inflammatory responses after are aberrant function reactive oxygen species accumulation. Our study demonstrates gates both activity to shape functions, changes which contribute abnormalities maladaptive inflammation diseases. Hu et al. role metabolism function, its dual under physiological pathological conditions mouse model stroke-induced

Language: Английский

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H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: Sept. 11, 2023

Cellular senescence serves as a fundamental and underlying activity that drives the aging process, it is intricately associated with numerous age-related diseases, including Alzheimer's disease (AD), neurodegenerative aging-related disorder characterized by progressive cognitive impairment. Although increasing evidence suggests senescent microglia play role in pathogenesis of AD, their exact remains unclear. In this study, we quantified levels lactic acid microglia, hippocampus tissues naturally aged mice AD models (FAD4T APP/PS1). We found were significantly elevated these cells compared to corresponding counterparts, which increased level pan histone lysine lactylation (Kla). aslo identified all Kla sites both H3K18 (H3K18la) Pan-Kla up-regulated modeling mice. demonstrated enhanced H3K18la directly stimulates NFκB signaling pathway binding promoter Rela (p65) NFκB1(p50), thereby upregulating senescence-associated secretory phenotype (SASP) components IL-6 IL-8. Our study provides novel insights into physiological function epigenetic regulatory mechanism regulates brain AD. Specifically, have H3K18la/NFκB axis critical player process modulating Targeting may be potential therapeutic strategy for delaying blunting SASP.

Language: Английский

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Metabolic reprogramming and polarization of microglia in Parkinson’s disease: Role of inflammasome and iron

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

Published: Aug. 10, 2023

Language: Английский

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Kaempferol, a potential neuroprotective agent in neurodegenerative diseases: From chemistry to medicine

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115215 - 115215

Published: July 24, 2023

Neurodegenerative diseases (NDDs) encompass a range of conditions that involve progressive deterioration and dysfunction the nervous system. Some common NDDs include Alzheimer's disease (AD), Parkinson's (PD), Huntington's (HD), amyotrophic lateral sclerosis (ALS). Although significant progress has been made in understanding pathological mechanisms recent years, development targeted effective drugs for their treatment remains challenging. Kaempferol is flavonoid whose derivatives kaempferol-O-rhamnoside, 3-O-β-rutinoside/6-hydroxykaempferol 3,6-di-O-β-d-glucoside, kaempferide. Emerging studies have suggested kaempferol its possess neuroprotective properties may potential therapeutic benefits NDDs. Here, we aimed to provide theoretical basis use clinical We systematically reviewed literature PubMed, Web Science, Science Direct databases until June 2022 using search terms "kaempferol," "kaempferol derivatives," "NDDs," "pharmacokinetics," "biosynthesis" according reporting items systematic review (PRISMA) standard. Based on combined results vivo vitro studies, summarize basic targets management AD, PD, HD, ALS. exert role mainly by preventing deposition amyloid fibrils (such as Aβ, tau, α-synuclein), inhibiting microglia activation, reducing release inflammatory factors, restoring mitochondrial membrane prevent oxidative stress, protecting blood-brain barrier, specific enzyme activities cholinesterase). are promising natural agents. By determining pharmacological mechanism, be new candidate

Language: Английский

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