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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PET Imaging of Neuroinflammation in Alzheimer’s Disease

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Sept. 16, 2021

Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with central pathologies patients animal models. Recent single-cell sequencing transcriptomics indicate dynamic disease-associated microglia astrocyte profiles disease. Mitochondrial 18-kDa translocator protein is most widely investigated target for imaging. New generation tracers improved performance been developed evaluated along tau amyloid assessing progression continuum. Given that not exclusively expressed glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 purinergic P2X7 P2Y12 fractalkine triggering receptor on myeloid cells 2, advanced glycation end products. Promising should demonstrate a higher specificity cellular locations exclusive expression or activation status (pro- anti-inflammatory) highly specific ligand to enable vivo brain In this review, we summarised recent advances development outlook promising future.

Language: Английский

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Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 28, 2023

Abstract Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases activated microglia mouse brain disease models does not change a non-human primate model or common human describe genetic divergence the gene promoter, consistent with hypothesis increase myeloid cells depends on transcription factor AP1 unique to subset of rodent species within Muroidea superfamily. Finally, we identify LCP2 TFEC as potential markers microglial humans. These data emphasise related different phenomena than mice, TSPO-PET signals humans reflect density inflammatory rather state.

Language: Английский

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Mitochondria-targeted photodynamic therapy triggers GSDME-mediated pyroptosis and sensitizes anti-PD-1 therapy in colorectal cancer

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(3), P. e008054 - e008054

Published: March 1, 2024

Background The effectiveness of immune checkpoint inhibitors in colorectal cancer (CRC) is limited due to the low tumor neoantigen load and infiltration most microsatellite-stable (MSS) tumors. This study aimed develop a mitochondria-targeted photodynamic therapy (PDT) approach provoke host antitumor immunity MSS-CRC elucidate underlying molecular mechanisms. Methods role mechanism PDT inhibiting CRC progression inducing pyroptosis were evaluated both vitro vivo. effects sensitization on PD-1 blockade also assessed CT26 4T1 tumor-bearing mouse models. Results Here, we report that using IR700DX-6T, photosensitizer targeting mitochondrial translocation protein, may trigger an response initiated by CRC. Mechanistically, IR700DX-6T-PDT produced reactive oxygen species light irradiation promoted downstream p38 phosphorylation active caspase3 (CASP3)-mediated cleavage gasdermin E (GSDME), subsequently pyroptosis. Furthermore, enhanced sensitivity cells blockade. Decitabine, demethylation drug used treat hematologic neoplasms, disrupted abnormal methylation pattern GSDME cells, efficacy IR700DX-6T-PDT, elicited potent combination with IR700DX-6T-PDT. Conclusion Our work provides clear understanding immunogenic cell death triggered PDT, offering new for enhancing

Language: Английский

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Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway

The Journal of Headache and Pain, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 27, 2025

Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly role mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in spinal dorsal horn play critical initiation persistence neuropathic pain. Among factors involved, TSPO (translocator protein) emerged as key regulator. Our experimental findings showed expression was upregulated during pain, accompanied dysfunction, specifically manifested impaired biogenesis, disrupted dynamics (including insufficient biogenesis fusion-related proteins, well significantly increased fission-related proteins), activation pyroptosis. Pharmacological upregulation TSPO, but not downregulation, effectively alleviated SNI-induced hypersensitivity, improving function reducing Immunofluorescence staining confirmed primarily localized astrocytes, mirrored protective effects on health prevention. PCR array suggested strong association between regulation pathway AMPK-PGC-1α. Notably, inhibition AMPK-PGC-1α abolished balance suppression. Furthermore, Mendelian randomization GWAS data indicated linked relief. Through drug screening, docking, behavioral assays, we identified zopiclone promising TSPO-targeting for treatment. In summary, this study enhances our interplay health, highlighting potential therapeutic target management.

Language: Английский

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The Common Alzheimer's Disease Research Ontology (CADRO) for biomarker categorization

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 1, 2025

Language: Английский

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A crosstalk between gut and brain in sepsis-induced cognitive decline

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

Published: May 23, 2022

Abstract Background Sepsis is a potentially fatal disease characterized by acute organ failure that affects more than 30 million people worldwide. Inflammation strongly associated with sepsis, and patients can experience impairments in memory, concentration, verbal fluency, executive functioning after being discharged from the hospital. We hypothesize sepsis disrupts microbiota–gut–brain axis homeostasis triggering cognitive impairment. This immune activation persists during treatment, causing neurological dysfunction survivors. Methods To test our hypothesis, adult Wistar rats were subjected to cecal–ligation perforation (CLP) or sham (non-CLP) surgeries. The animals [ 11 C]PBR28 positron emission tomography (PET)/computed (CT) imaging at 24 h 10 days CLP non-CLP At surgery, we evaluated gut microbiome, bacterial metabolites, cytokines, microglia, astrocyte markers. Ten induction, novel object recognition (NOR) Morris water maze (MWM) assess their learning memory. Results Compared control group, 24-h 10-day groups showed increased uptake, glial cells count, cytokine levels brain. show modulates villus length crypt depth, alpha beta microbial diversities, fecal short-chain fatty acids (SCFAs). In addition, surviving significant decline compared group. Conclusions Since several pharmacological studies have failed prevent impairment survivors, better understanding of function microbiota provide new avenues for treating patients.

Language: Английский

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The role of inflammation in neurodegeneration: novel insights into the role of the immune system in C9orf72 HRE-mediated ALS/FTD

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

Published: March 18, 2022

Abstract Neuroinflammation is an important hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). An inflammatory reaction to neuronal injury deemed vital for health homeostasis. However, a continued activation the response can be detrimental remaining neurons aggravate disease process. Apart from modifying role, some evidence suggests that neuroinflammation may also contribute upstream cause disease. In this review, we will first focus on role in pathogenesis chromosome 9 open reading frame 72 gene ( C9orf72 ) hexanucleotide repeat expansions (HRE)-mediated ALS/FTD (C9-ALS/FTD). Additionally, discuss ex vivo studies finally, briefly summarize trials progress anti-inflammatory therapies.

Language: Английский

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Microglia in epilepsy

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 185, P. 106249 - 106249

Published: Aug. 1, 2023

Epilepsy is one of most common chronic neurological disorders, and the antiseizure medications developed by targeting neurocentric mechanisms have not effectively reduced proportion patients with drug-resistant epilepsy. Further exploration cellular or molecular mechanism epilepsy expected to provide new options for treatment. Recently, more researches focus on brain network components other than neurons, among which microglia attracted much attention their diverse biological functions. As resident immune cells central nervous system, highly plastic transcription, morphology functional characteristics, can change dynamically in a context-dependent manner during progression In pathogenesis epilepsy, reactive interact epileptogenic performing crucial functions such as secretion soluble factors phagocytosis, thus continuously reshaping landscape epileptic microenvironment. Indeed, appear be both pro-epileptic anti-epileptic under different spatiotemporal contexts disease, rendering interventions biologically complex challenging. This comprehensive review critically summarizes pathophysiological role homeostasis alterations explores potential therapeutic modulatory targets microglia.

Language: Английский

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TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies

Brain Behavior and Immunity, Journal Year: 2023, Volume and Issue: 113, P. 415 - 431

Published: Aug. 3, 2023

The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity TSPO to identify brain processes appears vary greatly across disorders, disease stages, applied quantification methods. To advance potential biomarker evaluate inflammation anti-inflammatory therapies, better understanding its applicability disorders needed. We conducted transdiagnostic systematic review meta-analysis all vivo human case-control studies CNS. Specifically, we investigated direction, strength, heterogeneity associated with signal pre-specified regions, explored demographic methodological sources heterogeneity.We searched English peer-reviewed articles that differences. extracted details, outcomes, technical variables procedure. A random-effects was estimate standardized mean differences (SMD) lobar/whole-brain cortical grey matter (cGM), thalamus, cortico-limbic circuitry between different illness categories. Heterogeneity evaluated I2 statistic using subgroup meta-regression analyses radioligand generation, method, age, sex, publication year. Significance set at False Discovery Rate (FDR)-corrected P < 0.05.156 individual were included review, incorporating data 2381 healthy controls 2626 patients. 139 documented meta-analysable grouped into 11 Across categories, observed significantly higher cases compared cGM (n = 121 studies, SMD 0.358, PFDR 0.001, 68%), significant difference categories (P 0.004). increases only Alzheimer's (SMD 0.693, 64%) other neurodegenerative 0.929, 73%). Cortico-limbic 97 0.541, 67%) most prominent disease, mild cognitive impairment, mood multiple sclerosis. Thalamic involvement 79 0.393, 71%) sclerosis, chronic pain functional (all 0.05). Main outcomes systemic immunological viral infections, substance use schizophrenia traumatic injury not significant. identified between-study variance including strong effect method (explaining 25% variance; VT-based 0.000 versus reference tissue-based 0.630; F 20.49, df 1;103, 0.001), patient age (9% variance), generation (5% variance).This study first overarching findings humans several regions. robust specific types which widespread or focal depending on category. also found large horizontal (positive) shift estimates studies. Our results can support future optimize experimental design power calculations, by taking account type disorder, region-of-interest, radioligand, method.

Language: Английский

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