Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway DOI Creative Commons
Yanyu Zhai, Kaili Lu, Yuan Yuan

et al.

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Background Alzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting function. However, research about mechanism semaglutide as a therapeutic intervention in AD is sparse. Objective This study was to investigate efficacy transgenic mouse model pathology explored detailed by modulated neuroinflammatory processes. Methods Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with or vehicle for 8 weeks. Morris water maze test used assess recognition Pathology analysis performed detect deposition plaques. High-throughput sequencing applied specify mechanism. Microglia astrocyte activation assessed immunofluorescent staining. Inflammation cytokine levels evaluated enzyme-linked immunosorbent assay (ELISA). Related proteins pathway western blot. Results Semaglutide treatment attenuated Aβ accumulation enhanced APP/PS1 mice. Through transcriptomic profiling, immunohistochemical staining, ELISA, substantiated inhibit overactivation microglia astrocytes, well curtail secretion inflammatory mediators. Furthermore, robustly activated AMP-activated protein kinase (AMPK) suppressed toll-like 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing dampening cascade. Conclusions The results demonstrated that mitigated neuroinflammation decelerated advance

Language: Английский

Lysosomal acidification impairment in astrocyte-mediated neuroinflammation DOI Creative Commons
Jialiu Zeng,

Jonathan Indajang,

David Pitt

et al.

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 10, 2025

Abstract Astrocytes are a major cell type in the central nervous system (CNS) that play key role regulating homeostatic functions, responding to injuries, and maintaining blood-brain barrier. also regulate neuronal functions survival by modulating myelination degradation of pathological toxic protein aggregates. have recently been proposed possess both autophagic activity active phagocytic capability which largely depend on sufficiently acidified lysosomes for complete cellular cargos. Defective lysosomal acidification astrocytes impairs their resulting accumulation debris, excessive myelin lipids, aggregates, ultimately contributes propagation neuroinflammation neurodegenerative pathology. Restoration impaired represent new neuroprotective strategy therapeutic direction. In this review, we summarize pathogenic factors, including neuroinflammatory signaling, metabolic stressors, lipid mediated toxicity, contribute impairment associated dysfunction astrocytes. We discuss astrocyte-mediated primarily context diseases along with other brain injuries. then highlight re-acidification as restore well degradative capacity conclude providing future perspectives phagocytes crosstalk CNS cells impart or effects.

Language: Английский

Citations

0
Proteomic Profiling and Therapeutic Targeting of Oxidative Stress in Autoimmune Encephalitis DOI Creative Commons
Fan Zhang, Cong Zhang, Wei Sun

et al.

Journal of Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 75(2)

Published: March 19, 2025

Autoimmune encephalitis (AE) is an immune-mediated non-infectious disease, and novel robust biomarkers are needed to improve the diagnosis prognostic outcomes of AE. Oxidative stress a ubiquitous cellular process causing damage various biological molecules. The aim our study was understand clinical implication mechanism underlying oxidative in Liquid chromatography-mass spectrometry analysis conducted on serum eight patients with AE seven healthy controls, characterized. Experimental autoimmune (EAE) models were established C57BL/6 SJL mice for investigation therapeutic effect anti-oxidative N-acetylcysteine (NAC). We provided proteomic landscape identified antioxidant ALB, APOE, GPX3, SOD3 as diagnostic markers lowly expressed both central nervous system (CNS) EAE mice. NAC administration improved signs motor function alleviated nerve injury well lowered (decreased MDA content ROS accumulation elevated SOD activity GSH content). expressions by CNS Moreover, reduced tissue-resident CD4+ CD8+ T cells GFAP-marked astrocytes Iba-1-marked microglia mice, thus alleviating autoimmunity-mediated neuroinflammation. Our findings facilitate discovery stress-related reveal promise management.

Language: Английский

Citations

0
Transcriptome analysis reveals that the injection of mesenchymal stem cells remodels extracellular matrix and complement components of the brain through PI3K/AKT/FOXO1 signaling pathway in a neuroinflammation mouse model DOI Creative Commons

Zhihao Xu,

Keqin Liu,

Guoqing Zhang

et al.

Genomics, Journal Year: 2025, Volume and Issue: 117(3), P. 111033 - 111033

Published: March 22, 2025

Language: Английский

Citations

0
Central TYK2 inhibition identifies TYK2 as a key neuroimmune modulator DOI Creative Commons
Tyler P. Molitor,

Genki Hayashi,

Mei-Yao Lin

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(13)

Published: March 24, 2025

GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) sclerosis (MS). Impaired signaling within the central nervous system (CNS) may impart effects of P1104A MS. We deployed brain-penetrant inhibitors (cTYK2i) alongside peripherally restricted inhibitor (pTYK2i; BMS-986165) to untangle contributions inhibition diverse models neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated cTYK2i-treated EAE spinal cords circulating neurofilament light (NfL) plasma cerebral fluid (CSF). Additionally, an antibody-mediated mouse model primary progressive MS (PPMS). Finally, we demonstrate has robust impact on unique subset activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify key role for CNS regulating neuroinflammation solidify as potential therapeutic target

Language: Английский

Citations

0
Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway DOI Creative Commons
Yanyu Zhai, Kaili Lu, Yuan Yuan

et al.

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Background Alzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting function. However, research about mechanism semaglutide as a therapeutic intervention in AD is sparse. Objective This study was to investigate efficacy transgenic mouse model pathology explored detailed by modulated neuroinflammatory processes. Methods Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with or vehicle for 8 weeks. Morris water maze test used assess recognition Pathology analysis performed detect deposition plaques. High-throughput sequencing applied specify mechanism. Microglia astrocyte activation assessed immunofluorescent staining. Inflammation cytokine levels evaluated enzyme-linked immunosorbent assay (ELISA). Related proteins pathway western blot. Results Semaglutide treatment attenuated Aβ accumulation enhanced APP/PS1 mice. Through transcriptomic profiling, immunohistochemical staining, ELISA, substantiated inhibit overactivation microglia astrocytes, well curtail secretion inflammatory mediators. Furthermore, robustly activated AMP-activated protein kinase (AMPK) suppressed toll-like 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing dampening cascade. Conclusions The results demonstrated that mitigated neuroinflammation decelerated advance

Language: Английский

Citations

0