The cytosolic DNA‐sensing cGAS–STING pathway in neurodegenerative diseases

CNS Neuroscience & Therapeutics, Год журнала: 2024, Номер 30(3)

Опубликована: Март 1, 2024

Abstract Background With the widespread prevalence of neurodegenerative diseases (NDs) and high rates mortality disability, it is imminent to find accurate targets for intervention. There growing evidence that neuroimmunity pivotal in pathology NDs interventions targeting hold great promise. Exogenous or dislocated nucleic acids activate cytosolic DNA sensor cyclic GMP‐AMP synthase (cGAS), activating stimulator interferon genes (STING). The activated STING triggers innate immune responses then cGAS‐STING signaling pathway links abnormal acid sensing response. Recently, numerous studies have shown neuroinflammation regulated by plays an essential role NDs. Aims In this review, we summarized mechanism focused on inhibitors cGAS‐STING. Conclusion important pathogenesis Inhibiting may provide new measures treatment

Язык: Английский

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Synthesis, preclinical evaluation and pilot clinical study of a P2Y12 receptor targeting radiotracer [18F]QTFT for imaging brain disorders by visualizing anti-inflammatory microglia

Acta Pharmaceutica Sinica B, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

As the brain's resident immune cells, microglia perform crucial functions such as phagocytosis, neuronal network maintenance, and injury restoration by adopting various phenotypes. Dynamic imaging of these phenotypes is essential for accessing brain diseases therapeutic responses. Although numerous probes are available pro-inflammatory microglia, no PET tracers have been developed specifically to visualize anti-inflammatory microglia. In this study, we present an 18F-labeled tracer (QTFT) that targets P2Y12, a receptor highly expressed on [18F]QTFT exhibited high binding affinity P2Y12 (14.43 nmol/L) superior blood-brain barrier permeability compared other candidates. Micro-PET in IL-4-induced neuroinflammation models showed higher uptake lesions contralateral normal tissues. Importantly, specific could be blocked QTFT or antagonist. Furthermore, visualized mouse epilepsy, glioma, aging targeting aberrantly pilot clinical successfully located epileptic foci, showing enhanced radioactive signals patient with epilepsy. Collectively, studies suggest serve valuable diagnostic tool disorders overexpressed

Язык: Английский

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Modulating Neuroinflammation as a Prospective Therapeutic Target in Alzheimer’s Disease

Cells, Год журнала: 2025, Номер 14(3), С. 168 - 168

Опубликована: Янв. 22, 2025

The recent approval of lecanemab highlights that the amyloid beta (Aβ) protein is an important pathological target in Alzheimer’s disease (AD) and further emphasizes significance neuroinflammatory pathways regulating Aβ accumulation. Indeed, accumulation triggers microglia activation, which are key mediators neuroinflammation. inflammatory responses this process can lead to neuronal damage functional decline. Microglia secrete proinflammatory cytokines accelerate death release anti-inflammatory growth factors contributing recovery protection. Thus, play a dual role neurodegeneration neuroprotection, complicating their function AD. Therefore, elucidating complex interactions between protein, microglia, neuroinflammation essential for developing new strategies treating This review investigates receptors involved activating aims enhance understanding how these processes impact AD, as well they be regulated. also analyzed studies reported existing literature ongoing clinical trials. Overall, will contribute regulatory mechanisms therapies slow progression

Язык: Английский

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CPT1A ameliorates microglia-induced neuroinflammation via facilitating VDR succinylation

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 12, 2025

Neurodegenerative diseases, characterized by impairments in cognition, memory, and movement, are becoming increasingly prevalent due to population aging, posing a significant threat public health. Extensive evidence suggests that neuroinflammation, mediated microglia, plays crucial role the development of these diseases. Notably, vitamin D receptor (VDR) has been shown regulate microglia activation controlling function neuroprotective D. This study aims elucidate potential VDR modulating neuroinflammation. To mimic BV2 cells were treated with lipopolysaccharide (LPS) for 12 h. Enzyme-linked immunosorbent assays (ELISAs) used measure release cytokines, including IL-1β, IL-2, IL-6, IL-10, IL-12, MCP-1, TNF-α. Western blot performed assess relative protein expressions succinylation modifications. Co-immunoprecipitation (Co-IP) experiments conducted determine interaction between carnitine palmitoyltransferase 1A (CPT1A). Immunofluorescence staining was analyze localization VDR, CPT1A, COX-2, CD11b. Our findings demonstrated expression upregulated exposed LPS. Ectopic attenuated inflammatory response activation. We discovered (CPT1A) promoted succinylation. Further investigations revealed CPT1A enhanced stability binding lysine K117 being primary site. Importantly, depletion abrogated protective effects overexpression on microglia-mediated highlighted functioned as suppressor neuroinflammation facilitating succinylation, offering therapeutic targets management neurodegenerative

Язык: Английский

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Porphyromonas gingivalis: a potential trigger of neurodegenerative disease

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 14, 2025

Porphyromonas gingivalis ( P. ) is a gram-negative bacterium and the main causative agent of periodontitis, disease closely associated with development periodontal disease. The progression chronic infectious disease, intricately linked to inflammatory immune response. Inflammatory cytokines act on tissues via immunomodulation, resulting in destruction tissue. Recent studies have established connections between periodontitis various systemic diseases, including cardiovascular tumors, neurodegenerative diseases. Neurodegenerative diseases are neurological disorders caused by system dysfunction, Alzheimer’s Parkinson’s One characteristics an impaired response, which mediates neuroinflammation through microglial activation. Some shown association as primary culprit. can cross blood-brain barrier (BBB) or mediate injury variety pathways, gut-brain axis, thereby affecting neuronal growth survival participating onset However, comprehensive systematic summaries origin lacking. This article reviews summarizes relationship its possible regulatory mechanisms. review offers new perspectives into understanding highlights innovative approaches for investigating developing tailored medications treating conditions, particularly from viewpoint their .

Язык: Английский

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