Immunosenescence and Inflammaging: Mechanisms and Role in Diseases

Ageing Research Reviews, Год журнала: 2024, Номер 101, С. 102540 - 102540

Опубликована: Окт. 10, 2024

Язык: Английский

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Oral prodrug of a novel glutathione surrogate reverses metabolic dysregulation and attenuates neurodegenerative process in APP/PS1 mice

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

Опубликована: Янв. 17, 2025

ABSTRACT Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer’s disease (AD). Reduced glutathione levels in AD lead to increased stress, including glycation-induced pathology. Previously, we showed that accumulation reactive 1,2-dicarbonyls such as methylglyoxal, major precursor non-enzymatic glycation products, was reduced by function GSH-dependent glyoxalase-1 enzyme brain. In this two-pronged study, evaluate therapeutic efficacy an orally bioavailable prodrug our glyoxalase substrate, pro-ψ-GSH, for first time a transgenic mouse model. This delivers pharmacodynamically relevant brain concentrations ψ-GSH upon oral delivery. Chronic dosing pro-ψ-GSH effectively reverses cognitive decline observed APP/PS1 The successfully mirrors robust effects parent drug i.e., reducing amyloid pathology, neuroinflammation, and resultant neurodegeneration these mice. We also report metabolomics study treatment, which yields key biomarkers linked reversal AD-related dysregulation. Collectively, establishes viable, disease-modifying therapy paves way further preclinical advancement therapeutics. Metabolomic signatures identified could prove beneficial development treatment-specific clinically translatable biomarkers. GRAPHIC

Язык: Английский

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Influence of immune cells and inflammatory factors on Alzheimer’s disease axis: evidence from mediation Mendelian randomization study

BMC Neurology, Год журнала: 2025, Номер 25(1)

Опубликована: Фев. 5, 2025

Alzheimer's disease (AD) is one of the most common forms dementia in elderly, characterized by progressive neurodegeneration. While exact etiology AD remains unclear, immune inflammation known to play a significant role disease. This study utilized two-sample Mendelian randomization (MR) approach assess causal relationship between different types cells and AD, while considering inflammatory factors as intermediate variables. Data were collected from three sources: cell data (731 phenotypes), (48 cytokines 8,293 individuals), (35,274 cases, 59,163 controls). Multiple MR methods employed minimize bias, detailed descriptions instrumental variable selection statistical provided. The findings suggest potential relationships six well 13 factors. Additionally, two statistically found have with AD. Specifically, CD33-HLA DR + CD45 on may further influence regulating Interleukin-2 levels. provides valuable insights into immunoinflammatory pathogenesis offers partial guidance for development relevant interventions, thereby contributing beneficial information prevention treatment related diseases.

Язык: Английский

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From Plaques to Pathways in Alzheimer’s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(21), С. 11720 - 11720

Опубликована: Окт. 31, 2024

Alzheimer's disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates leading AD, has dominated research therapeutic strategies. failure recent Aβ-targeted therapies yield conclusive benefits necessitates further exploration AD pathology. This review proposes Mitochondrial-Neurovascular-Metabolic (MNM) integrates mitochondrial dysfunction, impaired neurovascular regulation, systemic metabolic disturbances as interrelated contributors pathogenesis. Mitochondrial hallmark leads oxidative stress bioenergetic failure. Concurrently, breakdown blood-brain barrier (BBB) cerebral blood flow, characterize dysregulation, accelerate neurodegeneration. Metabolic such glucose hypometabolism insulin resistance impair neuronal function survival. hypothesis highlights interconnectedness these pathways suggests strategies targeting health, integrity, regulation may offer more effective interventions. MNM addresses multifaceted aspects providing comprehensive framework for understanding progression developing novel approaches. approach paves way innovative could significantly improve outcomes millions affected worldwide.

Язык: Английский

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L-arginine mitigates choroid plexus changes in Alzheimer’s disease rat model via oxidative/inflammatory burden and behavioral modulation

Tissue and Cell, Год журнала: 2024, Номер 91, С. 102572 - 102572

Опубликована: Сен. 24, 2024

Язык: Английский

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Agaricus blazei extract FA-2b-β inhibits microglial pyroptosis by regulating the activation of the NF-κB signaling pathway mediated by Aβ 1-42 through the NLRP3 pathway

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Intracellular neurofibrillary tangles (NFTs) and neuroinflammatory plaques formed by amyloid-β (Aβ) are the main pathological features of AD. FA-2b-β, selenium mushroom extract from Qinba, had strong anti-inflammatory activity could protect against various inflammatory diseases regulating multiple signaling pathways. However, whether FA-2b-β can modulate Aβ₁₋₄₂-mediated neuroinflammation inhibiting NF-κB pathway has not been systematically investigated. The present study aimed to explore effect mechanism action on microglia inflammation. results showed that reduced release tumor necrosis factor-α (TNF-α) interleukin-1β (IL-1β), expression key proteins TLR4 p-IκB-α, NLRP3 Inflammasome associated with Caspase1. activation activates inflammasome leads increased pyroptosis protein GSDMD. Further, knockout intervention, respectively, in BV2 cells resulted corresponding reduction levels mediators, including NLRP3, Casp1, ASC, TNF-α, IL-1β. Mechanistically, inhibited nuclear factor kappa B (NF-κB) downregulated Nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) suppress cells. These findings suggested might represent potential therapeutic agent for anti-neuroinflammation.

Язык: Английский

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Sex-Specific Links Between Low Choline, Metabolic Dysfunction, and Neuropathology in Obesity: Insights from Humans and the 3xTg-AD Mouse Model of Alzheimer's disease.

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

Опубликована: Фев. 28, 2025

The growing prevalence of obesity, a risk factor for disorders such as Alzheimer's Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older is characterized by presence amyloid beta (Aβ) plaques, neurofibrillary tau tangles, neuroinflammation, all which contribute to impairment. Insulin resistance, common in both obesity AD, disrupts brain glucose metabolism accelerates neurodegeneration. Understanding factors that link these conditions could lead new strategies combating disease. Notably, B-like vitamin choline necessary fat has been shown help reduce incidence. However, ∼90% are deficient, decreases this nutrient have associated with decline. Here, we examined circulating levels, inflammation, metabolic dysfunction human participants (BMI > 30) compared normal BMIs (18.5-24.9), well 3xTg-AD mice, an model, fed choline-deficient diet throughout adulthood. Our results revealed obese exhibited significantly lower levels those healthy BMI. Lower correlated higher %Body increased markers insulin resistance. Elevated inflammatory cytokines were also seen mice diet, significant weight gain dysfunction. AD-like pathology was exacerbated deficient mice. These findings underscore relationship between low decline risk. Adequate intake may mitigate potentially preventing diseases. Obesity linked resistance (IR) systemic recognized disease (AD).Women exhibit men, individuals display than BMI.Lower body percentage, IR liver dysfunction, heightened inflammation.3xTg-AD experience considerable gain, pathology, resembling observed participants.

Язык: Английский

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Radix Hedysari Polysaccharides modulate the gut-brain axis and improve cognitive impairment in SAMP8 mice

International Journal of Biological Macromolecules, Год журнала: 2025, Номер 306, С. 141715 - 141715

Опубликована: Март 3, 2025

Язык: Английский

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IL-34/TREM2 modulates microglia-mediated inflammation and provides neuroprotection in a mouse model of sporadic Alzheimer's disease

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

Опубликована: Март 2, 2025

As a recently identified cytokine, interleukin-34 (IL-34) is predominantly produced by neurons and functions as modulator for glial functions. Emerging evidence indicates that IL-34 exerted neuroprotective effects in Alzheimer's disease (AD), but the underlying mechanism remained elusive. To uncover mechanisms which provides neuroprotection AD. Using senescence-accelerated mouse prone substrain 8 (SAMP8) mice, well-established model sporadic AD, we investigated dynamic changes brain concentrations during AD progression. Afterwards, SAMP8 mice received 4-week continuous intracerebroventricular infusion of IL-34. Morris water maze test was employed to assess spatial cognitive Neuronal synaptic markers, oxidative stress makers, pro-inflammatory cytokines activation markers brains were measured. Finally, amyloid-β (Aβ)42-stimulated primary microglia, lentivirus-mediated gene knockdown strategy co-immunoprecipitation assay utilized possible In revealed gradually decreased A rescued impairments, ameliorated neuronal damage, suppressed microglia-mediated inflammation mice. Aβ42-stimulated demonstrated first time microglial NLRP3 inflammasome release interacting with triggering receptor expressed on myeloid cells 2 (TREM2), key regulator These findings indicating IL-34/TREM2 signaling may represent novel therapeutic this devastating disease.

Язык: Английский

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Systemic Neuroprotection by Chlorogenic Acid: Antioxidant and Anti-inflammatory Evaluation in Early Neurodegeneration Induced by 3-Nitropropionic Acid in Mice

Neurochemical Research, Год журнала: 2025, Номер 50(2)

Опубликована: Март 4, 2025

Neurodegeneration is characterized by the progressive loss of neurons commonly attributed to neurological causes. Studies published over past two decades suggest that neurodegeneration may occur due systemic diseases compromise energy metabolism throughout body. This metabolic imbalance develops before clinically documented or inferred. It now accepted long-lasting oxidative stress and inflammation link with altered in Systemic prevention these factors reduce odds developing delay prevent its progression as individuals age. Chlorogenic acid (CGA) a polyphenol prevalent fruits vegetables exhibits antioxidant anti-inflammatory properties. serve neuroprotectant when consumed regularly onset neurodegeneration. To test this possibility, an experimental model striatal early induced administration 3-nitropropionic (3-NP) was used. toxin inhibits succinate dehydrogenase (SDH), disrupts electron flow leads increased production reactive oxygen species (ROS) pro-inflammatory environment. The severity symptoms 3-NP varies depending on dosage, duration exposure route. In brain, affects medium spiny basal ganglia less degree pyramidal from frontal cortex, feature observed Huntington's disease (HD). aim study investigate properties CGA 3-NP-induced significantly reduced lipid peroxidation promoted profile brain co-administered 3-NP. These results support could challenged environmental toxins disrupt mitochondrial function.

Язык: Английский

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