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

и другие.

Journal of Alzheimer s Disease, Год журнала: 2025, Номер unknown

Опубликована: Март 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

Язык: Английский

Modulating mTOR-dependent astrocyte substate transitions to alleviate neurodegeneration DOI
Liansheng Zhang, Zhengzheng Xu,

Zhiheng Jia

и другие.

Nature Aging, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Язык: Английский

Процитировано

4
Therapeutic targeting of obesity-induced neuroinflammation and neurodegeneration DOI Creative Commons
Jialiu Zeng,

Lenny Yi Tong Cheong,

Chih Hung Lo

и другие.

Frontiers in Endocrinology, Год журнала: 2025, Номер 15

Опубликована: Янв. 17, 2025

Obesity is a major modifiable risk factor leading to neuroinflammation and neurodegeneration. Excessive fat storage in obesity promotes the progressive infiltration of immune cells into adipose tissue, resulting release pro-inflammatory factors such as cytokines adipokines. These inflammatory mediators circulate through bloodstream, propagating inflammation both periphery central nervous system. Gut dysbiosis, which results leaky intestinal barrier, exacerbates plays significant role linking pathogenesis neurodegeneration gut-brain/gut-brain-liver axis. Inflammatory states within brain can lead insulin resistance, mitochondrial dysfunction, autolysosomal increased oxidative stress. disruptions impair normal neuronal function subsequently cognitive decline motor deficits, similar pathologies observed neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease. Understanding underlying disease mechanisms crucial for developing therapeutic strategies address defects these metabolic pathways. In this review, we summarize provide insights different strategies, methods alter gut lifestyle changes, dietary supplementation, well pharmacological agents derived from natural sources, that target obesity-induced

Язык: Английский

Процитировано

2
Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium DOI Creative Commons
Jonathan R. Soucy,

Erika A. Aguzzi,

Julie Cho

и другие.

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Сен. 21, 2023

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach reverse from if newly introduced neurons can reestablish functional retinal thalamic circuits. In theory, RGCs might be repopulated through transplantation of stem cell-derived or via induction endogenous transdifferentiation. The Repopulation, Stem Cell Transplantation, Optic Nerve Regeneration (RReSTORe) Consortium was established address challenges associated with repair visual pathway neuropathy. 2022, RReSTORe initiated ongoing international collaborative discussions advance field has identified five critical areas focus: (1) development differentiation, (2) Transplantation methods models, (3) survival, maturation, host interactions, (4) Inner wiring, (5) Eye-to-brain connectivity. Here, we discuss most pertinent questions that exist on path clinical translation suggest experimental directions propel this work going forward. Using these subtopic discussion groups (SDGs) as framework, multidisciplinary approaches restore diseased by leveraging groundbreaking insights developmental neuroscience, biology, molecular optical imaging, animal models neuropathy, immunology & immunotolerance, neuropathology neuroprotection, materials science biomedical engineering, neuroscience. While significant hurdles remain, Consortium's efforts provide comprehensive roadmap for advancing hold potential transformative progress restoring patients suffering neuropathies.

Язык: Английский

Процитировано

31
Emerging roles of astrocytes as immune effectors in the central nervous system DOI
Theodore M. Fisher, Shane A. Liddelow

Trends in Immunology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 1, 2024

Язык: Английский

Процитировано

9
Defining the molecular identity and morphology of glia limitans superficialis astrocytes in vertebrates DOI Creative Commons
Philip Hasel, Melissa Cooper, Anne E Marchildon

и другие.

Cell Reports, Год журнала: 2025, Номер 44(3), С. 115344 - 115344

Опубликована: Фев. 20, 2025

Язык: Английский

Процитировано

1
PLXNB1 and other signaling drives a pathologic astrocyte state contributing to cognitive decline in Alzheimer's Disease DOI Open Access
Natacha Comandante-Lou,

Tsering Lama,

Kevin W. Chen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Alzheimer's disease (AD) is marked by the coordinated emergence of disease-associated cell states across multiple types. Here, we first performed a meta-analysis single-nucleus transcriptomic (snRNAseq) data from 869 brains diverse decedents, confirming critical role an SLC38A2 high SMTN CACNA1D astrocyte subset, Astrocyte 10 (Ast10), in AD and aging-related cognitive decline. We then investigated signaling drivers Ast10's aging brain, focusing on interactions among microglial astrocytic subsets. Analysis snRNAseq prioritized set ligands receptors that are robustly predictive Ast10 proportions participants, confirm our predictions studies. Independent validation with spatial transcriptomics reveals striking colocalization these signature brain tissue, but not other states. Genetic ablation top receptor PLXNB1 murine human iPSC-derived astrocytes decreased signature, its regulatory role. Finally, find may contribute to decline through synaptic loss associated independent AD. Thus, regulators potential points convergence for neurodegenerative mechanisms be promising targets therapeutic development preserve function.

Язык: Английский

Процитировано

1
Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research DOI Creative Commons
Eun Sun Jung, Hayoung Choi, Inhee Mook‐Jung

и другие.

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Март 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Язык: Английский

Процитировано

1
Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice DOI
Liansheng Zhang,

Zhiheng Jia,

Qiang Wu

и другие.

Nature Metabolism, Год журнала: 2023, Номер 5(10), С. 1787 - 1802

Опубликована: Сен. 7, 2023

Язык: Английский

Процитировано

15
Defining the molecular identity and morphology ofglia limitans superficialisastrocytes in mouse and human DOI Creative Commons
Philip Hasel, Melissa Cooper, Anne E Marchildon

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Апрель 6, 2023

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and are, at least part, associated with their anatomical location can be restricted to strategically important domains. Here, we report forming glia limitans superficialis, outermost border of brain spinal cord, specialized astrocyte identified by single marker: Myocilin (Myoc). We show Myoc+ cover entire cord surface, exhibit an atypical morphology, evolutionarily conserved from rodents humans. Identification this will advance our understanding CNS homeostasis potentially targeted for therapeutic intervention combat peripheral inflammatory effects on CNS.

Язык: Английский

Процитировано

13
Neuroinflammatory gene expression profiles of reactive glia in the substantia nigra suggest a multidimensional immune response to alpha synuclein inclusions DOI Creative Commons
Anna C. Stoll,

Christopher J. Kemp,

Joseph R. Patterson

и другие.

Neurobiology of Disease, Год журнала: 2024, Номер 191, С. 106411 - 106411

Опубликована: Янв. 21, 2024

Parkinson's disease (PD) pathology is characterized by alpha-synuclein (α-syn) aggregates, degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc), and neuroinflammation. The presence reactive glia correlates with deposition pathological α-syn early-stage PD. Thus, understanding neuroinflammatory response microglia astrocytes to synucleinopathy may identify therapeutic targets. Here we gene expression profile SNpc during early rat pre-formed fibril (PFF) model. Rats received intrastriatal injection PFFs immune genes was quantified droplet digital PCR (ddPCR), after which fluorescent situ hybridization (FISH) used localize or SNpc. Genes previously associated (Cd74, C1qa, Stat1, Axl, Casp1, Il18, Lyz2) (C3, Gbp2, Serping1) were significantly upregulated SN PFF injected rats. Localization near aggregates identified a unique aggregate microglial upregulation Cd74, Cxcl10, Rt-1a2, Grn, Csf1r, Tyrobp, C3, Serping1 Fcer1g. Importantly, significant Cd74 C3 only observed following PFFs, not monomer, confirming specificity aggregation. also localized Interestingly, at 2- 4-months post-PFF, but 6-months post-PFF. We Rt1-a2 Cxcl10 neurons. Cumulatively our results dynamic, yet reproducible

Язык: Английский

Процитировано

5