Role of 11β-Hydroxysteroid Dehydrogenase and Mineralocorticoid Receptor on Alzheimer’s Disease Onset: A Systematic Review

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1357 - 1357

Published: Feb. 6, 2025

The role of 11β-HSD1 in Alzheimer’s disease (AD) has garnered significant attention due to its involvement glucocorticoid metabolism, neuroinflammation, and cognitive decline. This review explores the current understanding AD, examining genetic, preclinical, clinical research. Genetic studies have identified polymorphisms that may influence AD risk, although findings remain inconsistent. Mechanistically, promotes neurodegeneration through dysregulation activity, contributing hippocampal atrophy, amyloid plaque formation, tau pathology. Preclinical shown inhibitors offer neuroprotective effects, including enhanced function, reduced inflammation, improved mitochondrial activity. However, trials, those involving ABT-384 Xanamem, produced mixed results, with no substantial improvements despite effective enzyme inhibition. These inconsistencies highlight complexity challenges translating preclinical into outcomes. Moreover, while inhibition holds therapeutic potential, other strategies targeting autophagy, signaling are also being explored. Ongoing research is focusing on optimizing inhibitors, identifying biomarkers for patient selection, investigating combination therapies enhance treatment efficacy. Ultimately, 11β-HSD1’s presents a promising target, but further required fully understand potential managing disease.

Language: Английский

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Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 13, 2025

Abstract The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion exocrine digestive enzymes. Complex interactions signaling mechanisms between functions of pancreas play a crucial role in maintaining metabolic homeostasis overall health. Compelling evidence indicates direct indirect crosstalk parts, influencing development diseases affecting both. From developmental perspective, parts share same origin—the “tip-trunk” domain. In certain circumstances, pancreatic cells may transdifferentiate into endocrine-like cells, insulin-secreting cells. Additionally, several diseases, including cancer, pancreatitis, diabetes, exhibit potential relevance to both functions. Endocrine communicate directly cytokines or indirectly regulating immune microenvironment. This affects onset progression these diseases. review summarizes history milestones findings related their embryonic development, phenotypic transformations, roles health disease, endocrine-exocrine from perspective therapeutic targets. Elucidating regulatory provide novel insights for understanding treatment

Language: Английский

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Context‐Sensitive Conscious Interpretation and Layer‐5 Pyramidal Neurons in Multistable Perception

Brain and Behavior, Journal Year: 2025, Volume and Issue: 15(3)

Published: March 1, 2025

There appears to be a fundamental difference between the two ways of how an object becomes perceptually experienced. One occurs when preconscious object-specifying sensory data processing crosses certain threshold so that constituents depiction become consciously The other already experienced features interpreted as belonging visual category. Surprisingly, experimental facts about neural markers conscious access gathered far do not allow us distinguish mechanisms responsible for these varieties. A cortical multicompartment layer-5 pyramidal neuron-based generic model is presented in order conceptualize possible mechanistic solution explanatory cul-de-sac. To support argument, review pertinent research compiled associated with from studies where physically invariant perceptual stimuli have underwent alternative interpretation(s) by brain. Recent developments newly emerging field cellular psycho(physio)logy are introduced, offering hypothetical distinguishing subserving content experience and interpretation. single cell-based approach brain process correlates perception added value beyond traditional inter-areal connectivity-based theoretical stances.

Language: Английский

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Network pharmacology approach to unravel the neuroprotective potential of natural products: a narrative review

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

Published: April 25, 2025

Language: Английский

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Identification of novel risk genes for Alzheimer’s disease by integrating genetics from hippocampus

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 11, 2024

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative ailment, presently lacking a definitive cure. Given that primary medications for AD patients in early or middle stages demonstrate optimal efficacy, it becomes crucial to delve into identification of risk genes associated with onset. In our study, we compiled and integrated three transcriptomics datasets (GSE48350, GSE36980, GSE5281) originating from hippocampus 37 66 healthy controls (CTR) comprehensive bioinformatics analysis. Comparative analysis CTR revealed 25 up-regulated 291 down-regulated AD. Those were notably enriched processes related transmission transport synaptic signals. Intriguingly, 27 differentially expressed implicated also correlated Braak stage, establishing connection various immune cell types exhibit differences AD, including cytotoxic T cells, neutrophils, CD4 Th1, Th2, Tfh. Significantly, Cox model, constructed using nine feature genes, effectively stratified samples (HR = 2.72, 95% CI 1.94 ~ 3.81, P 3.6e–10), highlighting their promising potential assessment. conclusion, investigation sheds light on novel intricately linked onset progression offering biomarkers detection this debilitating condition. This study contributes valuable insights toward enhancing strategies preventing treating

Language: Английский

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Characteristics and Transcriptomic Analysis of Cholinergic Neurons Derived from Induced Pluripotent Stem Cells with APP Mutation in Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 101(2), P. 637 - 649

Published: Aug. 27, 2024

Background: The cholinergic hypothesis is one of the main theories that describe pathogenesis Alzheimer’s disease (AD). Cholinergic neurons degenerate early and are severely damaged in AD. Despite extensive research, causes neuron damage underlying molecular changes remain unclear. Objective: This study aimed to explore characteristics transcriptomic derived from human induced pluripotent stem cells (iPSCs) with APP mutation. Methods: Peripheral blood mononuclear patients AD healthy individuals were reprogrammed into iPSCs. iPSCs differentiated neurons. stained, neurotoxically tested, electrophysiologically transcriptomically analyzed. Results: iPSCs-derived a patient carrying mutation displayed enhanced susceptibility Aβ1-42-induced neurotoxicity, characterized by severe neurotoxic effects, such as cell body coagulation neurite fragmentation. exhibited electrophysiological impairments neuronal death after 21 days culture group. Transcriptome analysis disclosed 883 differentially expressed genes (DEGs, 420 upregulated 463 downregulated) participating several signaling pathways implicated pathogenesis. To assess reliability RNA sequencing, expression 16 target DEGs was validated using qPCR. Finally, 8 core different types brain analyzed AlzData database. Conclusions: In this study, mutations exhibit reminiscent neurodegenerative disease. revealed corresponding pathways, providing potential biomarkers therapeutic targets for advancing research.

Language: Английский

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Predicting Alzheimer's Cognitive Resilience Score: A Comparative Study of Machine Learning Models Using RNA-seq Data

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

Published: Aug. 26, 2024

Alzheimer's disease (AD) is an important research topic. While amyloid plaques and neurofibrillary tangles are hallmark pathological features of AD, cognitive resilience (CR) a phenomenon where function remains preserved despite the presence these features. This study aimed to construct compare predictive machine learning models for CR scores using RNA-seq data from Religious Orders Study Memory Aging Project (ROSMAP) Mount Sinai Brain Bank (MSBB) cohorts. We evaluated support vector regression (SVR), random forest, XGBoost, linear, transformer-based models. The SVR model exhibited best performance, with contributing genes identified Shapley additive explanations (SHAP) scores, providing insights into biological pathways associated CR. Finally, we developed tool called gene analyzer (REGA), which visualizes SHAP interpret contributions individual REGA available at https://igcore.cloud/GerOmics/REsilienceGeneAnalyzer/.

Language: Английский

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Impaired spatial coding and neuronal hyperactivity in the medial entorhinal cortex of APP^NL-G-Fmice

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

Published: Nov. 26, 2024

Abstract The progressive accumulation of amyloid beta (Aβ) pathology in the brain has been associated with aberrant neuronal network activity and poor cognitive performance preclinical mouse models Alzheimer’s disease (AD). Presently, our understanding mechanisms driving pathology-associated dysfunction impaired information processing remains incomplete. Here, we assessed impact advanced Aβ on spatial medial entorhinal cortex (MEC) 18-month App NL-G-F/NL- G-F knock-in (APP KI) mice as they explored contextually novel familiar open field arenas a two-day, four-session recording paradigm. We tracked single unit firing across all sessions found that scores were decreased MEC neurons from APP KI versus those age-matched C57BL/6J controls. representations also impacted mice. Border cell preferences unstable periodicity putative grid cells was disrupted. In contrast, border Control intact stable sessions. then quantified stability maps by utilizing metric based Earth Mover’s Distance (EMD). evidence for increased instability spatially-tuned Controls when re-exposed to environments exposed environment. Additionally, decoding analysis units revealed deficits position speed coding session comparisons. Finally, mild hyperactive phenotype appeared be driven narrow-spiking (putative interneurons). These findings tie Aβ-associated dysregulation disruptions may underlie certain AD.

Language: Английский

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