Recent Insights on the Role of Nuclear Receptors in Alzheimer’s Disease: Mechanisms and Therapeutic Application

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1207 - 1207

Published: Jan. 30, 2025

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad array of biological processes, including inflammation, lipid metabolism, cell proliferation, and apoptosis. Among the diverse family NRs, peroxisome proliferator-activated (PPARs), estrogen receptor (ER), liver X (LXR), farnesoid (FXR), retinoid (RXR), aryl hydrocarbon (AhR) have garnered significant attention for their roles in neurodegenerative diseases, particularly Alzheimer’s disease (AD). NRs influence pathophysiology AD through mechanisms such as modulation amyloid-beta (Aβ) deposition, regulation inflammatory pathways, improvement neuronal function. However, dual role progression, where some may exacerbate while others offer therapeutic potential, presents critical challenge application treatment. This review explores functional diversity highlighting involvement AD-related processes discussing prospects NR-targeting strategies. Furthermore, key challenges, necessity precise identification beneficial detailed structural analysis molecular dynamics simulations, further investigation NR AD, tau pathology autophagy, also discussed. Collectively, continued research is essential to clarify ultimately facilitating potential use diagnosis, prevention, treatment AD.

Language: Английский

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Hyperintensity of the left piriform cortex and amygdala on T2-weighted FLAIR images in patients with probable Alzheimer’s disease correlates with cerebral cortical atrophy

Acta Radiologica Open, Journal Year: 2025, Volume and Issue: 14(2)

Published: Feb. 1, 2025

Background The left piriform cortex and amygdala (PC&A) tend to be slightly hyperintense relative the right PC&A on T2-weighted fluid-attenuated inversion recovery (T2W-FLAIR) images in patients with probable Alzheimer’s disease (pAD). This likely represents antecedent thus advanced degeneration of PC&A. Purpose To investigate relationship between hyperintensities cerebral cortical atrophy magnetic resonance (MR) voxel-based morphometry pAD discuss how this finding could relate AD progression. Material Methods Patients ( n = 47; age range 68–93 years, mean 80.8 ± 6.7 years; 14 men 33 women) who underwent T2W-FLAIR imaging MR morphometric study using a specific regional analysis system for (VSRAD) were retrospectively examined. measure signal intensity ratios (L-PC&A/R-PC&A), regions interest (ROIs) set transaxial which both PC&As most broadly depicted; ROIs defined as large possible. Correlations L-PC&A/R-PC&A medial temporal lobe (MTLCA) well whole (WCCA) VSRAD determined. Correlation was also Results correlated MTLCA (r 0.375, p .010, 95% confidence interval [CI] 0.095–0.600) WCCA 0.576, < .001, CI 0.343–0.742). did not correlate 0.013, .932, −0.282–0.305). Conclusion Left-sided dominance appeared accelerate progression stages.

Language: Английский

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The dual role of microglia in Alzheimer’s disease: from immune regulation to pathological progression

Frontiers in Aging Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: March 27, 2025

Alzheimer’s disease (AD) is a widespread neurodegenerative disorder and one of the major challenges for public health. Despite extensive research, role microglia in AD remains complex dual. The aim this review to summarize most recent advances research regarding dual concerning both immunomodulation pathological progression by considering mechanisms activation microglia, effects on Aβ clearance, tau pathology, impacts due genetic variations microglial functions. Among these findings are status M1 M2 phenotypes, crucial that variants like TREM2 have modulating response microglia. This describes how modulation signaling pathway might be exploited therapeutically treatment underlines relevance personalized medicine approach.

Language: Английский

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Inhibitory Potential of the Drimane Sesquiterpenoids Isotadeonal and Polygodial in the NF-kB Pathway

Molecules, Journal Year: 2025, Volume and Issue: 30(7), P. 1555 - 1555

Published: March 31, 2025

Inflammation contributes to the onset and development of many diseases, including neurodegenerative caused by activation microglia, leading neurological deterioration. Nuclear factor-κB (NF-κB) is one most relevant pathways for identifying anti-inflammatory molecules. In this study, polygodial isotadeonal, two drimane sesquiterpene dialdehydes, were isolated from Drimys winteri, a medicinal tree Mapuche people in Chile. Isotadeonal, or epi-polygodial, was obtained epimerization basic media (60% yield, Na2CO3, r/t, 24 h). Both sesquiterpenoids evaluated on NF-κB pathway, with result that isotadeonal inhibited phosphorylation IκB-α at 10 μM higher potency Western blotting. The final inhibition pathway using SEAP reporter (secreted alkaline phosphatase) THP-1 cells. Isotadeonal than polygodial, quercetin, CAPE (phenethyl ester caffeic acid). silico analysis suggests α-aldehyde adopts more stable conformation active pocket polygodial.

Language: Английский

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Carvacrol/thymol derivatives as highly selective BuChE inhibitors with anti-inflammatory activities: Discovery and bio-evaluation

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108430 - 108430

Published: April 1, 2025

Language: Английский

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Novelties on Neuroinflammation in Alzheimer’s Disease–Focus on Gut and Oral Microbiota Involvement

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(20), P. 11272 - 11272

Published: Oct. 19, 2024

Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through microbiota–gut–brain axis, including Alzheimer’s disease (AD). This review aims to provide a comprehensive synthesis recent findings on involvement neuroinflammatory processes associated with AD, emphasizing novel insights therapeutic implications. reveals that dysbiosis AD patients’ is linked heightened peripheral central inflammatory responses. Specific bacterial taxa, such as Bacteroides Firmicutes gut, well Porphyromonas gingivalis cavity, are notably altered leading significant changes microglial activation cytokine production. Gut alterations increased intestinal permeability, facilitating translocation endotoxins like lipopolysaccharides (LPS) into bloodstream exacerbating by activating brain’s toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, short-chain fatty acids (SCFAs) amyloid peptides, can cross blood-brain barrier modulate While microbial amyloids may contribute amyloid-beta aggregation brain, certain SCFAs butyrate exhibit anti-inflammatory properties, suggesting potential avenue mitigate neuroinflammation. not only highlights critical pathology but also offers ray hope modulating could represent strategy for reducing slowing progression.

Language: Английский

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Photobiomodulation regulates astrocyte activity and ameliorates scopolamine-induced cognitive behavioral decline

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Sept. 20, 2024

Introduction The pathophysiological mechanism of Alzheimer’s disease (AD) has not been clearly identified, and effective treatment methods have yet established. Scopolamine causes cholinergic dysfunction in the brain, including accumulation amyloid-beta plaques, thereby increasing oxidative stress neuroinflammation, mimicking AD. Glial cells such as astrocytes recently identified possible biomarkers for Photobiomodulation (PBM) elicits a beneficial biological response tissues. PBM effects on central nervous system (CNS) widely researched, astrocyte activity. Methods In present study, was performed using light at near-infrared wavelength 825 nm. Morris water maze Y-maze tests were employed to evaluate cognitive function decline scopolamine-induced memory model its improvement with PBM. addition, alteration mitogen-activated protein kinase (MAPK) pathway immunofluorescence expression levels active observed hippocampus, which is one areas affected by AD, action Results A reduction neuronal cell death hippocampus caused scopolamine Moreover, MAPK pathway-related marker changes glial fibrillary acidic (an marker) PBM-treated group. Finally, significant correlations between functional histological results found, validating results. Discussion These findings indicate possibility behavioral due CNS alteration, mimics This could be related neuroinflammatory modulation altered

Language: Английский

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Optimization of microRNA Target Sequence Arrangement in AAV Vectors Dramatically Enhances Specificity and Efficiency of Transgene Expression in Cortical Microglia

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

Published: Nov. 6, 2024

Abstract Microglia play a critical role in diseases such as Alzheimer’s and stroke, making them significant target for therapeutic intervention. However, due to their immune functions detecting combating viral invasion, efficient gene delivery microglia remains challenging. We achieved specific using an adeno- associated virus (AAV) vector designed this purpose. This microglia-targeting AAV includes the mouse microglia/macrophage-specific ionized calcium-binding adaptor molecule 1 (mIba1) promoter, green fluorescent protein (GFP), microRNA sequences (miR.Ts), woodchuck hepatitis posttranscriptional regulatory element (WPRE), polyadenylation (polyA) signal, positioned between inverted terminal repeats. When miR.Ts were placed downstream of WPRE (between polyA), expression occurred not only but also substantial number neurons. when upstream GFP WPRE) or on both sides WPRE, neuronal was significantly suppressed, resulting selective microglia. Notably, positioning over 90% specificity more than 60% efficiency transgene three weeks after administration. enabled GCaMP microglia, facilitating real-time monitoring calcium dynamics microglial process activity cortex. Additionally, intravenous administration with blood-brain barrier-penetrant AAV-9P31 capsid variant resulted extensive selectively throughout brain. These findings establish system robust tool long-term, specific,

Language: Английский

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