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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Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration

Science Advances, Journal Year: 2023, Volume and Issue: 9(10)

Published: March 8, 2023

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia the brain of old C57BL/6 mice (>18 months old) demonstrate that comparison to young mice, one-third are AF, characterized profound changes lipid iron content, phagocytic activity, oxidative stress. Pharmacological depletion eliminated AF following repopulation reversed microglial dysfunction. Age-related neurological deficits neurodegeneration after traumatic injury (TBI) were attenuated lacking microglia. Furthermore, increased lysosomal burden, accumulation persisted for up 1 year TBI, modified APOE4 genotype, chronically driven phagocyte-mediated Thus, may reflect a pathological state aging associated phagocytosis neurons myelin inflammatory can be further accelerated TBI.

Language: Английский

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Role of hypoxia in cellular senescence

Pharmacological Research, Journal Year: 2023, Volume and Issue: 194, P. 106841 - 106841

Published: June 28, 2023

Senescent cells persist and continuously secrete proinflammatory tissue-remodeling molecules that poison surrounding cells, leading to various age-related diseases, including diabetes, atherosclerosis, Alzheimer's disease. The underlying mechanism of cellular senescence has not yet been fully explored. Emerging evidence indicates hypoxia is involved in the regulation senescence. Hypoxia-inducible factor (HIF)- 1α accumulates under hypoxic conditions regulates by modulating levels markers p16, p53, lamin B1, cyclin D1. Hypoxia a critical condition for maintaining tumor immune evasion, which promoted driving expression genetic factors (such as p53 CD47) while triggering immunosenescence. Under conditions, autophagy activated targeting BCL-2/adenovirus E1B 19-kDa interacting protein 3, subsequently induces p21WAF1/CIP1 well p16Ink4a increases β-galactosidase (β-gal) activity, thereby inducing Deletion p21 gene activity response regulator poly (ADP-ribose) polymerase-1 (PARP-1) level nonhomologous end joining (NHEJ) proteins, repairs DNA double-strand breaks, alleviates Moreover, associated with intestinal dysbiosis an accumulation D-galactose derived from gut microbiota. Chronic leads striking reduction amount Lactobacillus D-galactose-degrading enzymes gut, producing excess reactive oxygen species (ROS) bone marrow mesenchymal stem cells. Exosomal microRNAs (miRNAs) long noncoding RNAs (lncRNAs) play important roles miR-424-5p are decreased hypoxia, whereas lncRNA-MALAT1 increased, both induce present review focuses on recent advances understanding role effects HIFs, PARP-1, microbiota, exosomal mRNA hypoxia-mediated cell specifically discussed. This our provides new clues anti-aging processes treatment aging-related diseases.

Language: Английский

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Emerging role of senescent microglia in brain aging-related neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Feb. 20, 2024

Abstract Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain pathogenesis of these conditions remains inadequately understood. Cellular senescence considered to contribute cellular dysfunction inflammaging. According threshold theory senescent cell accumulation, vulnerability associated with rates generation clearance within brain. Given role microglia in eliminating cells, accumulation may lead acceleration aging, contributing inflammaging increased diseases. In this review, we propose idea that microglia, which notably vulnerable could potentially serve as central catalyst progression The are emerging promising target mitigating

Language: Английский

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The role of cellular senescence in neurodegenerative diseases

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(8), P. 2393 - 2408

Published: May 15, 2024

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of hallmarks (p16 p21) elevated β-galactosidase activity in vitro vivo ND models. These contribute to the deposition β-amyloid tau-protein tangles. Selective clearance SASP regulation by inhibiting p38/mitogen-activated protein kinase nuclear factor kappa B signaling attenuate load prevent tangle deposition, thereby improving cognitive performance AD mouse In addition, telomere shortening, a biomarker, is associated with increased risks. Telomere dysfunction causes senescence, stimulating tumor necrosis factor-α, IL-1β secretions. The forced telomerase activators prevents yielding considerable neuroprotective effects. This review elucidates mechanism pathogenesis, suggesting strategies eliminate or restore normal phenotype for treating such diseases.

Language: Английский

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Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 2, 2024

Abstract Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence PD remains to be defined. Methods Long culture-induced replicative model 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature model, mouse of were investigate the metformin vivo vitro. Immunofluorescence staining flow cytometric analyses performed evaluate mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA substantia nigra pars compacta regions specifically reduce astrocytic cGAS expression clarify potential molecular mechanism by which inhibited PD. Results showed that vitro mice. Mechanistically, normalized function DNA release through mitofusin 2 (Mfn2), leading inactivation cGAS-STING, delayed prevented neurodegeneration. Mfn2 overexpression reversed inhibitory role cGAS-STING activation senescence. More importantly, ameliorated dopamine neuron injury behavioral deficits mice reducing accumulation senescent via inhibition activation. Deletion abolished suppressive Conclusions This work reveals delays inhibiting Mfn2-cGAS suggest is promising therapeutic agent diseases.

Language: Английский

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The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: March 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Language: Английский

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Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Feb. 4, 2025

Abstract Background Cellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role cholesterol homeostasis, and expression trafficking altered APOE4 AD models. However, the ABCA1 senescence associated with remains unclear. Methods We examined association between human postmortem brain samples using transcriptomic, histological, biochemical analyses. Unbiased proteomic screening was performed identify proteins that mediate trafficking. created knock out cell lines mouse models validate cholesterol-induced mTORC1 activation senescence. Additionally, we used APOE4-TR mice induced pluripotent stem (iPSC) explore cholesterol-ABCA1-senescence pathways. Results Transcriptomic profiling dorsolateral prefrontal cortex from Religious Order Study/Memory Aging Project (ROSMAP) cohort revealed upregulation transcriptome signatures AD, which correlated oxysterol levels. Immunofluorescence immunoblotting analyses confirmed increased lipofuscin-stained lipids brains mTOR phosphorylation. Discovery proteomics identified caveolin-1, sensor accumulation, as key promoter endolysosomal Greater caveolin-1 observed brains. Oxysterol were regulated by lysosomal trapping. Treatment cyclodextrin reduced levels, lysosome trapping, activation, attenuated neuroinflammation markers. In iPSC-derived astrocytes, reduction inflammatory responses. Conclusions expression, contributing dysfunction This study provides novel insights into how metabolism accelerates features pathway identifies therapeutic targets mitigate these processes.

Language: Английский

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Immune responses in the Parkinson's disease brain

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 168, P. 105700 - 105700

Published: March 19, 2022

Immune changes occur in all neurodegenerative conditions, but there are significant differences between diseases. For Parkinson's disease (PD), the immune system involvement is still being identified with considerable promise for therapeutic targeting. Post-mortem analyses of PD patient brains and pre-clinical cell rodent models identify increased inflammation brain an elevation central peripheral pro-inflammatory cytokines. The cells involved include activated microglia surrounding degenerating neurons, currently thought to be neuroprotective early stages detrimental at later stages. Very different astrocytic reactions found compared other a loss normal astrocyte functions contributing neurotoxic or dysfunctional phenotype (rather than classical astrogliosis conditions). Astrocytes also actively clearing α-synuclein away from vulnerable eventual accumulation their cytoplasm promotes response contributes spreading pathology. Infiltration occurs brain, particularly T monocytes. Both CD4 CD8 regions loss, cytotoxic occurring earliest helper progression. Current evidence points towards infiltrating monocytes as playing role neuron death. Further characterisation successive molecular both resident invading will provide targets modification.

Language: Английский

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The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson’s disease via LCN2-dependent astrocyte senescence

Cell Death and Differentiation, Journal Year: 2023, Volume and Issue: 30(10), P. 2280 - 2292

Published: Aug. 26, 2023

Language: Английский

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