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: Agents of the CNS Pro-Inflammatory Response

Cells, Journal Year: 2020, Volume and Issue: 9(7), P. 1717 - 1717

Published: July 17, 2020

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though research spans over century, last two decades have increased our understanding exponentially. Here, we discuss phenotypic transformation from homeostatic towards reactive microglia, initiated specific ligand binding pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering expressed on myeloid cells-2 (TREM2), as well signaling pathways triggered such caspase-mediated response. Additionally, new disciplines epigenetics and immunometabolism provided us with more holistic view how changes in DNA methylation, microRNAs, metabolome may influence This review aimed current knowledge different angles, recent highlights role exosomes spreading neuroinflammation emerging techniques positron emission tomography (PET) scanning use human generated induced pluripotent stem cells (iPSCs). Finally, also thoughts impact

Language: Английский

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Molecular regulations of circadian rhythm and implications for physiology and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 8, 2022

The term "circadian rhythms" describes endogenous oscillations with ca. 24-h period associated the earth's daily rotation and light/dark cycle. Such rhythms reflect existence of an intrinsic circadian clock that temporally orchestrates physiological processes to adapt internal environment external cues. At molecular level, consists multiple sets transcription factors resulting in autoregulatory transcription-translation feedback loops. Notably, addition their primary role as generator rhythm, biological plays a key controlling functions almost all tissues organs. It regulates several intracellular signaling pathways, ranging from cell proliferation, DNA damage repair response, angiogenesis, metabolic redox homeostasis, inflammatory immune response. In this review, we summarize findings showing crosstalk between some describing scenario wherein reciprocal regulation impinges upon aspects mammalian physiology. Moreover, based on evidence indicating can be challenged by environmental factors, social behaviors, well pre-existing pathological conditions, discuss implications misalignment human pathologies, such cancer diseases. Accordingly, disruption rhythm has been reported affect are relevant Expanding our understanding field represents intriguing transversal medicine challenge order establish precision medicine.

Language: Английский

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Circadian rhythms in neurodegenerative disorders

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 18(1), P. 7 - 24

Published: Nov. 10, 2021

Language: Английский

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Circadian disruption and sleep disorders in neurodegeneration

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Feb. 13, 2023

Abstract Disruptions of circadian rhythms and sleep cycles are common among neurodegenerative diseases can occur at multiple levels. Accumulating evidence reveals a bidirectional relationship between disruptions diseases. Circadian disruption disorders aggravate neurodegeneration in turn disrupt sleep. Importantly, various increase the risk Thus, harnessing biology findings from preclinical translational research is importance for reducing improving symptoms quality life individuals with via approaches that normalize context precision medicine. In this review, we discuss implications by summarizing both human animal studies, focusing on links prevalent forms neurodegeneration. These provide valuable insights into pathogenesis suggest promising role circadian-based interventions.

Language: Английский

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Circadian Rhythm, Microglia-Mediated Neuroinflammation, and Alzheimer’s Disease

Neuroscience & Biobehavioral Reviews, Journal Year: 2025, Volume and Issue: 170, P. 106044 - 106044

Published: Feb. 4, 2025

Language: Английский

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Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

Aging Cell, Journal Year: 2019, Volume and Issue: 19(2)

Published: Dec. 4, 2019

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is circadian system. Although patients with AD are known to have abnormal rhythms and suffer sleep disturbances, role molecular clock in regulating amyloid-beta (Aβ) pathology still poorly understood. Here, we explored how repressors REV-ERBα β affected Aβ clearance mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels master protein BMAL1 more rapidly phagocytosed fibrillary Aβ1-42 (fAβ1-42 ) than CT12. directly drives transcription REV-ERB proteins, which implicated microglial activation. Interestingly, pharmacological inhibition REV-ERBs small molecule antagonist SR8278 or genetic knockdown REV-ERBs-accelerated uptake fAβ1-42 increased BMAL1. also promoted polarization toward a phagocytic M2-like phenotype P2Y12 receptor expression. Finally, constitutive deletion Rev-erbα 5XFAD model decreased amyloid plaque number size prevented plaque-associated increases disease-associated markers including TREM2, CD45, Clec7a. Altogether, our work suggests novel strategy controlling neuroinflammation by targeting provides insights into AD.

Language: Английский

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Targeting REV-ERBα for therapeutic purposes: promises and challenges

Theranostics, Journal Year: 2020, Volume and Issue: 10(9), P. 4168 - 4182

Published: Jan. 1, 2020

REV-ERBα (NR1D1) is a circadian clock component that functions as transcriptional repressor.Due to its role in direct modulation of metabolic genes, regarded an integrator cell metabolism with clock.Accordingly, first proposed drug target for treating sleep disorders and syndromes (e.g., dyslipidaemia, hyperglycaemia obesity).Recent years studies uncover rather broad pathological conditions including local inflammatory diseases, heart failure cancers.Moreover, involved regulation has implications chronopharmacology.In the meantime, recent have witnessed discovery array new ligands most which pharmacological activities vivo.In this article, we review regulatory various types diseases discuss underlying mechanisms.We also describe newly discovered old ones together their targeting potential.Despite well-established effects animals (preclinical studies), no progress been made regarding translation clinical trials.This implies certain challenges associated development ligands.In particular, potential related safety (or adverse effects) bioavailability.For development, it advocated should be targeted treat locally distributed, avoiding on other tissues.

Language: Английский

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Chronic sleep deprivation altered the expression of circadian clock genes and aggravated Alzheimer's disease neuropathology

Brain Pathology, Journal Year: 2021, Volume and Issue: 32(3)

Published: Oct. 20, 2021

Circadian disruption is prevalent in Alzheimer's disease (AD) and may contribute to cognitive impairment, psychological symptoms, neurodegeneration. This study aimed evaluate the effects of environmental genetic factors on molecular clock establish a link between circadian rhythm disturbance AD. We investigated pathological chronic sleep deprivation (CSD) APPswe /PS1ΔE9 transgenic mice their wild-type (WT) littermates for 2 months evaluated expression levels genes rhythm-related nuclei. Our results showed that CSD impaired learning memory, further exaggerated progression AD mice. Furthermore, caused abnormal Bmal1, Clock, Cry1 nuclei experimental mice, these changes are more significant Abnormal suggested affected by APP/PS1 mutations. In addition, tau phosphorylation was found retrosplenial cortex, which co-located with alteration BMAL1 protein level. Moreover, level tyrosine hydroxylase locus coeruleus WT significantly increased after CSD. There be potential clock, Aβ pathology, tauopathy, noradrenergic system. The this provided new insights into development

Language: Английский

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The circadian clock protein Rev-erbα provides neuroprotection and attenuates neuroinflammation against Parkinson’s disease via the microglial NLRP3 inflammasome

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: June 6, 2022

Circadian disturbance is a common nonmotor complaint in Parkinson's disease (PD). The molecular basis underlying circadian rhythm PD poorly understood. Neuroinflammation has been identified as key contributor to pathology. In this study, we explored the potential link between core clock molecule Rev-erbα and microglia-mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome pathogenesis.We first examined diurnal rhythms changes inflammatory cytokines expression SN of MPTP-induced mice. Further, used BV2 cell investigate impacts on NLRP3 microglial polarization induced by 1-methyl-4-phenylpyridinium (MPP+) αsyn pre-formed fibril. role regulating activation via NF-κB pathway was then explored. Effects SR9009 against activation, microgliosis nigrostriatal dopaminergic degeneration striatum mice were studied detail.BV2 cell-based experiments revealed through pathways. oscillation gene substantia nigra (SN) disappeared mice, well morphology. significantly elevated. Furthermore, neurons loss system partially reversed SR9009, selective agonist. addition, effectively reduced glial system.These observations suggest that protein plays an essential attenuating neuroinflammation pathology, provides therapeutic target for treatment.

Language: Английский

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