Characterization of preclinical Alzheimer’s disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: March 8, 2024

Abstract Background The key to the prevention and treatment of Alzheimer’s disease (AD) is be able predict diagnose AD at preclinical or early stage, but lack a model critical factor that causes this problem remain unresolved. Methods We assessed 18 monkeys in vivo evaluation pro-inflammatory cytokines pathological biomarkers ( n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, negative control (NC) 17, FPG < mg/dL). Levels was measured by ELISA Simoa Technology, respectively. evaluated ex for AD-like pathology 6 T2DM 22.17, 126 3 NC 14.67, To evaluate features brains monkeys, we levels Aβ, phospho-tau, neuroinflammation using immunohistochemistry, which further confirmed deposition Aβ plaques Bielschowsky’s silver, Congo red, Thioflavin S staining. Synaptic damage neurodegeneration were immunofluorescence. Results found not only increased such as tumor necrosis factor-α (TNF-α) peripheral blood (PB) brain also changes PB decreased β-amyloid (Aβ) 42 Aβ40 levels. Most notably, observed including plaque deposition, p-tau from neuropil thread pre-neurofibrillary tangles (NFTs), even appearance extracellular NFT. Microglia activated resting state an amoeboid. Astrocytes showed marked hypertrophy number cell bodies protrusions. Finally, impairment postsynaptic membrane no neuronal death. Conclusions Overall, elevated intracerebral inflammation, positive body fluids, developing brain, tau pathology, glial activation, partial synaptic damage, degeneration death compared healthy normal group. Hereby, consider with elevation factors can potentially regarded model.

Language: Английский

---

Circulating biomarkers of inflammaging and Alzheimer’s disease to track age-related trajectories of dementia: Can we develop a clinically relevant composite combination?

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102257 - 102257

Published: March 2, 2024

Language: Английский

---

Biomarker Profile in Peripheral Blood Cells Related to Alzheimer’s Disease

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Abstract In a healthy brain, neuroinflammation, controlled by the main intermediary for immune response microglia and astrocytes, contributes to maintain physiological functions such as secretion of neurotrophic factors, removal cell tau amyloid-β (Aβ) debris, local homeostasis. When becomes chronic, it can become pathological fuel causing glial cells malfunction not perform their function clearing resulting in further damage neurons. Multiple studies highlight that an intense crosstalk is activated between peripheral blood white (PBWCs) central nervous system (CNS). Nevertheless, how PBWC be carriers biomarkers CNS neuropathological states still far completely known. this work, we aimed observe content could related moderate-severity DAT order have early signals from neurodegeneration brain initiate. Protein analysis been performed Mild Cognitive Impairment (MCI) patients respect those controls differently expressed proteins investigated. Our data showed deregulation pathways involved since MCI level deregulated considered markers onset progression.

Language: Английский

---

Anti-inflammatory effects of 64Zn-aspartate is accompanied by cognitive improvements in rats with Aβ1-40-induced alzheimer disease

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 24, 2025

Language: Английский

---

Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer’s Disease

Biomedicines, Journal Year: 2023, Volume and Issue: 11(12), P. 3232 - 3232

Published: Dec. 6, 2023

Alzheimer's disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also neurofibrillary tangles (NFTs). Tau Aβ complexes spread the entorhinal cortex brain interconnected regions, where they bind pattern recognition receptors on microglia astroglia trigger inflammation neurotoxicity that ultimately lead neurodegeneration clinical AD. Systemic initiated Aβ's egress into circulation, which may be secondary microglial activation can confer both destructive reparative actions. Microglial pathways downstream drivers Aβ/NFT neurotoxicity, including inflammatory regulators, are primary targets for AD therapy. Osteopontin (OPN), an cytokine biomarker AD, implicated in clearance toxicity, activation, inflammation, considered a potential therapeutic target. Here, using most relevant works literature, we review contextualize evidence central role OPN associated

Language: Английский

---

GRK5KO Mouse Mirrors Mild Cognitive Impairment due to Alzheimer’s Disease

Published: April 12, 2024

Alzheimer’s disease (AD) poses a significant public health challenge due to its irreversible and progressive nature while lack of cure. As potential strategy combat AD, prevention becomes increasingly attractive. Mild Cognitive Impairment AD (MCI-AD) represents critical transitional stage between normal age-related cognitive decline more severe conditions, occurring just before dementia onset. Unfortunately, there is currently no established animal model that accurately recapitulates MCI-AD characteristics. While many laboratories have traditionally used normally aged wild-type animals as experimental models, this approach falls short in representing the inherently worse state compared aging. To address gap, we introduce an model—a transgenic mouse line with genetic inactivation G protein-coupled receptor kinase-5 (GRK5), commonly known GRK5 knockout (GRK5KO) mouse. These GRK5KO mice exhibit amnesia, deficits, increased β-amyloid levels, neurofibrillary tangle (NFT) immunopositive axonopathy, hippocampal neurodegenerative changes. Importantly, these pathological alterations predominantly impact entorhinal, transentorhinal, cortices, aligning human criteria Braak II progression. Notably, female show approximately 2.5 times NFT-positive axonopathy than males, mirroring higher prevalence cases women. Collectively, existing data strongly supports qualified for studying MCI-AD.

Language: Английский

---

The association between arthritis and cognitive function impairment in the older adults: Based on the NHANES 2011–2014

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(9), P. e0310546 - e0310546

Published: Sept. 27, 2024

Objective Arthritis has been postulated as a prevalent potential risk factor for the emergence of dementia and cognitive impairment. This conjecture prompted an examination correlation between arthritis impairment using National Health Nutrition Examination Survey (NHANES) repository. The analysis was meticulously adjusted confounders such age assorted systemic comorbidities, to ensure robustness in results obtained. Methods Among 2,398 adults aged 60 years above, logistic regression cubic spline models were employed elucidate relationship performance. assessed utilizing tests Immediate Recall test (IRT), Delayed (DRT), Animal Fluency Test (AFT), Digit Symbol Substitution (DSST). Results In our investigation, total 19931 individuals analyzed, among which patients (12.03%) identified with arthritis. Subjects inflammation had lower DSST AFT scores compared healthy group, indicating decline. After adjusting all covariates, significantly associated higher by modeling (OR: 0.796, 95% CI: 0.649–0.975; OR: 0.769, 0.611–0.968). Conclusion Our underscores linkage prevalence within nationally representative US older adults.

Language: Английский

---

Interleukin‐6 induces cognitive impairment via toll‐like receptor 4 (TLR4)‐mediated neuroinflammation and neurodegeneration in mice with chronic kidney disease

Neuroprotection/Neuroprotection (Chichester, England. Print), Journal Year: 2024, Volume and Issue: 2(3), P. 203 - 215

Published: Sept. 1, 2024

Abstract Backgrounds Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease (CKD) leads to cognitive impairment. However, the underlying mechanism requires further investigation. Herein, a mouse model of CKD was established using conventional 5/6 nephrectomy. We aimed examine relationship between impairment elucidate mechanisms. Methods Cognitive behavior assessed Morris water maze, novel object recognition test, fear conditioning test. Further experiments were also conducted investigate molecular Results Our clinical data revealed decrease function among patients with CKD, accompanied by elevated plasma levels pro‐inflammatory cytokines. A positive correlation cytokine concentrations serum creatinine levels, as well significant dysfunction, observed. Correlation analyzes hippocampal positively correlated dysfunction mice. Furthermore, 20 mg/mL interleukin‐6 (IL‐6) significantly decreased HT22 cell activity vitro. Further, cells treated IL‐6 showed increased expression toll‐like receptor 4 (TLR4) myeloid differentiation primary response gene 88 (MyD88), thereby inducing nuclear factor kappa‐B p65 inflammatory pathway mitochondria‐dependent apoptosis. The TLR4 cytokines hippocampus. knockdown antagonized IL‐6‐mediated pro‐apoptotic effects cells. mice inflammation number neuron dendrites, thus ameliorated Conclusion These results suggest triggers activation induce neuroinflammation neurodegeneration ultimately culminate

Language: Английский

---

Is amnestic mild cognitive impairment a neuro-immune condition?

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 6, 2024

Abstract Background The pathophysiology of amnestic Mild Cognitive Impairment (aMCI) is largely unknown, although some papers found signs immune activation. Aims To assess the cytokine network in aMCI after excluding patients with major depression (MDD) and to examine profiles quantitative (qMCI) distress symptoms old age (DSOA) scores. Methods A cross-sectional study was conducted on 61 Thai participants 60 healthy adults (both without MDD). Bio-Plex Pro human 27-plex test kit LUMINEX 200 were used assay cytokines/chemokines/growth factors fasting plasma samples. Results characterized by significant general immnosuppression, reductions T helper 1 (Th)1 cell growth profiles, immune-inflammatory responses system, interleukin (IL)1β, IL6, IL7, IL12p70, IL13, GM-CSF, MCP-1 as compared controls. These 7 cytokines/chemokines exhibit neuroprotective effects at physiologic concentrations. In multivariate analyses, three neurotoxic chemokines, CCL11, CCL5, CXCL8, emerged predictors aMCI. Logistic regression showed that best predicted combining IL1β, MCP-1, years education (all inversely associated) CCL5 (positively associated). We 38.2% variance qMCI score explained (inversely DSOA not associated any data. Discussion dysbalance between lowered levels cytokines relative increases chemokines are key Future MCI research should always control for confounding affective symptoms.

Language: Английский

---

Is Amnestic Mild Cognitive Impairment a Neuro-Immune Condition?

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 2, 2024

Objectives The pathophysiology of amnestic Mild Cognitive Impairment (aMCI) is largely unknown, although some papers found signs immune activation. To assess the cytokine network in aMCI after excluding patients with major depression (MDD) and to examine profiles quantitative (qMCI) distress symptoms old age (DSOA) scores. Design: A case-control study. Setting: Department Psychiatry a University Hospital, Bangkok, Thailand. Participants : 61 Thai participants 60 healthy adults (both without MDD). Measurements Bio-Plex Pro human 27-plex test kit was used assay cytokines/chemokines/growth factors fasting plasma samples. Results characterized by significant general immunosuppression, reductions T helper 1 (Th)1 cell growth profiles, immune-inflammatory responses system, interleukin (IL)1β, IL6, IL7, IL12p70, IL13, GM-CSF, MCP-1. These 7 cytokines/chemokines exhibit neuroprotective effects at physiologic concentrations. In multivariate analyses, three neurotoxic chemokines, CCL11, CCL5, CXCL8, emerged as predictors aMCI. Logistic regression showed that best predicted combining IL1β, MCP-1, years education (all inversely associated) CCL5 (positively associated). We 38.2% variance qMCI score explained (inversely DSOA not associated any data. Discussion dysbalance between lowered levels cytokines relative increases chemokines are key Future MCI research should always control for confounding affective symptoms.

Language: Английский

---