A review and analysis of key biomarkers in Alzheimer’s disease

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

Published: Feb. 20, 2024

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects over 50 million elderly individuals worldwide. Although the pathogenesis of AD not fully understood, based on current research, researchers are able to identify potential biomarker genes and proteins may serve as effective targets against AD. This article aims present comprehensive overview recent advances in identification, with highlights use various algorithms, exploration relevant biological processes, investigation shared biomarkers co-occurring diseases. Additionally, this includes statistical analysis key reported research literature, identifies intersection AD-related gene sets from databases such AlzGen, GeneCard, DisGeNet. For these sets, besides enrichment analysis, protein–protein interaction (PPI) networks utilized central among overlapping genes. Enrichment protein network tissue-specific connectedness GTEx database performed multiple groups Our work has laid foundation for better understanding molecular mechanisms more accurate identification markers.

Language: Английский

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Altered glia-neuron communication in Alzheimer’s Disease affects WNT, p53, and NFkB Signaling determined by snRNA-seq

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 7, 2024

Alzheimer's disease is the most common cause of dementia and characterized by amyloid-β plaques, tau neurofibrillary tangles, neuronal loss. Although loss a primary hallmark disease, it known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis health through neuron-glia glial crosstalk. Many signaling pathways have been proposed to be dysregulated in including WNT, TGFβ, p53, mTOR, NFkB, Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia neurons.

Language: Английский

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Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: Jan. 2, 2024

Abstract Alzheimer’s Disease (AD) is a disorder characterized by cognitive decline, neurodegeneration, and accumulation of amyloid plaques tau neurofibrillary tangles in the brain. Dysregulation epigenetic histone modifications may lead to expression transcriptional programs that play role either protecting against disease genesis or worsening pathology. One such modification, acetylation H3 lysine residue 27 (H3K27ac), primarily localized genomic enhancer regions promotes active gene transcription. We previously discovered H3K27ac be more abundant AD patient brain tissue compared brains age-matched non-demented controls. In this study, we use iPSC-neurons derived from familial patients with an precursor protein (APP) duplication (APP Dup neurons) as model study functional effect lowering CBP/P300 enzymes catalyze H3K27ac. found homeostatic amyloid-reducing genes were upregulated APP neurons lowered reduce H3K27ac, which led decreased numerous these genes, along increased extracellular secretion toxic amyloid-β species, Aβ(1–42). Our findings suggest epigenomic acetylation, including drives compensatory genetic response AD-associated insults, specifically those resulting duplication, thus mitigating pathology neurons.

Language: Английский

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Neuropathological stage‐dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory‐related omics signatures to computational repurposing of drug candidates

Brain Pathology, Journal Year: 2024, Volume and Issue: 34(4)

Published: March 7, 2024

Abstract Alzheimer's disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss, and behavioral deterioration. Albeit substantial progress has been made in characterizing AD‐associated molecular cellular events, there unmet clinical need for new therapies. In this study, tract proteotyping performed controls AD subjects ( n = 17/group) showed a Braak stage‐dependent proteostatic impairment accompanied modulation amyloid precursor protein tau functional interactomes. To implement computational repurposing drug candidates with capacity to reverse AD‐related omics signatures (OMSs), we generated consensual OMSs database compiling differential datasets obtained mass‐spectrometry or RNA‐sequencing derived from initial across axis. Using Connectivity Map‐based approach, PKC, EGFR, Aurora kinase, Glycogen synthase CDK inhibitors were top pharmacologic classes capable restore multiple OMSs, whereas compounds targeted activity inhibit PI3K, Insulin‐like growth factor 1 (IGF‐1), microtubules, Polo‐like kinase (PLK) represented family drugs detrimental potential induce gene expression changes. validate therapeutic effects proposed drugs, vitro assays performed. These validation experiments revealed that pretreatment human neuron‐like SH‐SY5Y cells EGFR inhibitor AG‐1478 neuroprotective effect against hydrogen peroxide‐induced damage while Reversine reduced amyloid‐beta (Aβ)‐induced neurotoxicity. Taken together, our data pointed out may be useful as substrates propose novel treatments AD.

Language: Английский

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Revealing the potential therapeutic mechanism of Lonicerae Japonicae Flos in Alzheimer’s disease: a computational biology approach

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Nov. 13, 2024

Background Alzheimer’s disease (AD) is a degenerative brain without cure. Lonicerae Japonicae Flos (LJF), traditional Chinese herbal medicine, possesses neuroprotective effect, but its mechanisms for AD are not well understood. This study aimed to investigate potential targets and constituents of LJF against AD. Methods Network pharmacology bioinformatics analyses were performed screen compounds targets. Gene Expression Omnibus (GEO) datasets related patients used core differential expression. expression profiling interactive analysis (GEPIA) was validate the correlation between target genes major causative The receiver operating characteristic (ROC) evaluate predictive efficacy based on GEO datasets. Molecular docking dynamics simulation conducted analyze binding affinities effective with Results showed that 112 intersection identified. Bioinformatics displayed 32 putative identified from Only eight differentially expressed Finally, six MAPK8, CTNNB1, NFKB1, EGFR, BCL2, NFE2L2 progression had good ability ROC analyses. elucidated component lignan interacted β-carotene CTNNB1 β-sitosterol hederagenin berberine EGFR baicalein BCL2. Conclusion Through comprehensive analysis, this revealed (MAPK8, NFE2L2) practical components (lignan, β-carotene, β-sitosterol, hederagenin, berberine, baicalein) involved in mechanism action Our work demonstrated effectively treats through multi-component multi-target properties. findings will establish theoretical basis expanded application treatment and, hopefully, can guide more advanced experimental research future.

Language: Английский

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Systems Pharmacology Approach and Experiment Evaluation Reveal Pterocarpus Mildbraedii (Fabaceae) Intervention for Counteracting Behavioral Changes and Neuroinflammatory and Oxidative Stress Markers Against Lps-Induced Alzheimer's Disease in Rats

Published: Jan. 1, 2025

Ethnopharmacological relevance: Pterocarpus mildbraedii was believed to have multiple benefits, including antioxidant, antipyretic, antalgic, anti-convulsant, and anxiolytic effects. Previous studies reported that water extract (Pm) contained secondary metabolites able cross the BBB. However, Pm's systemic mechanism targets for neuroinflammation remain largely unexplored.Aim of study: This research used a systems pharmacology approach experiment evaluation reveal potential protective effects Pm against neuroinflammation, oxidative stress, behavioral changes in an LPS-induced Alzheimer's disease (AD) rat model.Materials methods: integrated network analysis experimental verification evaluate pharmacological PM AD systematically. Swiss Target Prediction, GeneCards, STRING databases were employed identify targets. The interaction between active components hub confirmed via molecular docking. GO KEGG pathway analyses also carried out. Further, vitro bioassays explore anti-inflammatory antioxidant activities and, finally, vivo neuroinflammatory stress markers.Results: Network docking revealed primarily regulates signaling pathways such as ESR1, ESR2, BACE1, MAPK1, TLR4, IL6, GSK3B through like liquiritigenin pterocarptriol. identified significant action AD, nitrogen metabolism VEGF pathway. In vitro, demonstrated their properties, along with inhibitory on AchE BchE. Behavioral tests showed LPS exposure impaired exploratory behavior, spatial learning, increased anxiety rats, correlating brain, marked by elevated MDA NO levels, decreased CAT, SOD, GSH levels. raised TNF-α IL-6 levels while reducing dopamine, serotonin, AChE activity. Notably, treatment significantly mitigated improved activity, restored neurotransmitter animals.Conclusion: paper established P. could inhibit its components, targets, pathways. milbraedii may be candidate treatment.

Language: Английский

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Integrating GWAS and Transcriptome Data through PrediXcan and Multimodal Deep Learning to Reveal Genetic Basis and Novel Drug Repositioning Opportunities for Alzheimer's Disease

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Alzheimer’s Disease (AD) is the leading cause of dementia, imposing significant economic and social burdens. Although genome-wide association studies (GWAS) have identified approximately 70 risk loci, functional mechanisms underlying AD remain unclear. In this study, we integrated GWAS summary statistics from Jiang et al. with gene expression data GTEx project using S-PrediXcan method, encompassing 61 brain-related traits across 49 tissues. Comprehensive analysis five traits, including family history AD, highlighted key genes such as APOE, APOC1, TOMM40, which play crucial roles in cholesterol metabolism, immune response, neuroinflammation. Validation ROSMAP dataset confirmed these phenotypes. Furthermore, developed AD-MIF, a novel deep multi-layer information fusion model that integrates multi-omics data, achieving 10-20% improvement AUC performance for predicting AD-related compared to traditional models. Gene enrichment emphasized importance pathways metabolism response pathogenesis AD. Additionally, drug repositioning candidate drugs, Dasatinib Sirolimus, may alleviate progression by reducing neuroinflammation clearing senescent cells. Our findings advance understanding genetic architecture improve predictive models, propose potential therapeutic drugs.

Language: Английский

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Exploring the Kidney-Brain Crosstalk: Biomarkers for Early Detection of Kidney Injury-Related Alzheimer’s Disease

Journal of Inflammation Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 827 - 846

Published: Jan. 1, 2025

The phenomenon of "kidney-brain crosstalk" has stimulated scholarly inquiry into the correlations between kidney injury (KI) and Alzheimer's disease (AD). Nonetheless, precise interactions shared mechanisms KI AD have yet to be fully investigated. primary goal this study was investigate link AD, with a specific focus on identifying diagnostic biomarkers for KI-related AD. first step present use Mendelian randomization (MR) analysis followed by verification in vivo vitro experiments. Subsequently, bioinformatics machine learning techniques were used identify KI-associated ferroptosis-related genes (FRGs) which validated following Moreover, relationship hub immune infiltration assessed using CIBERSORT, potential drugs or small molecules associated core identified via DGIdb database. MR showed that may risk factor Experiments combination D-galactose aluminum chloride found induce both ferroptosis emerging as bridge facilitate crosstalk Besides, we EGFR RELA significant value. These are NK_cells_resting B_cells_memory could targeted intervention treating gefitinib plumbagin. Our elucidates an important pathway kidney-brain crosstalk. Notably, plumbagin therapeutic candidates intervening targeting RELA.

Language: Английский

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Integrative bioinformatic approach reveals novel melatonin-related biomarkers for Alzheimer’s disease

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

Published: Feb. 4, 2025

Background: Melatonin (MLT) can improve mitophagy, thereby ameliorating cognitive deficits in Alzheimer's disease (AD) patients. Hence, our research focused on the potential value of MLT-related genes (MRGs) AD through bioinformatic analysis. Methods: First, key cells single-cell dataset GSE138852 were screened out based proportion annotated and Fisher's test between control groups. The differentially expressed (DEGs) cell GSE5281 datasets identified, MRGs selected via weighted gene coexpression network After intersecting two sets DEGs MRGs, we performed Mendelian randomization analysis to identify causally related AD. Biomarkers further ascertained receiver operating characteristic curve (ROC) expression GSE48350. Furthermore, set enrichment analysis, immune infiltration correlation with metabolic pathways conducted, as well construction a regulator molecular docking. Results: According Fisher test, oligodendrocytes regarded due their excellent abundance dataset, which there 281 overlapping 3,490 550 GSE5281, four found be AD, namely, G protein-coupled receptor, family C, group 5, member B (GPRC5B), Methyltransferase-like protein 7 A (METTL7A), NF-κB inhibitor alpha (NFKBIA) RAS association domain 4(RASSF4). Moreover, GPRC5B, NFKBIA RASSF4 deemed biomarkers, except for METTL7A, because indistinctive might involved oxidative phosphorylation, adipogenesis heme metabolism. T helper type 17 cells, natural killer CD56dim significantly correlated biomarkers. Transcription factors (GATA2, POU2F2, NFKB1, etc.) regulate Finally, discovered that all biomarkers could bind MLT strong binding energy. Conclusion: Our study identified three novel RASSF4, providing approach investigation treatment

Language: Английский

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Exploring the Efficacy and Target Genes of Atractylodes Macrocephala Koidz Against Alzheimer’s Disease Based on Multi-Omics, Computational Chemistry, and Experimental Verification

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(2), P. 118 - 118

Published: Feb. 11, 2025

To unveil the efficacy and ferroptosis-related mechanisms of Atractylodes Macrocephala Koidz (AMK) against Alzheimer's disease (AD), which is most widespread neurodegenerative disease. Gene set variation analysis (GSVA) scores were used to investigate relationship between ferroptosis AD. Logistic regression with seven feature selections a deep learning model utilized identify potential targets AMK based on transcriptomic data from multiple tissues. A transcriptome-wide association study (TWAS), summary-data-based mendelian randomization (SMR), (MR) validate causal target genes AD risk. single-gene gene enrichment (GSEA) was employed biological pathways associated genes. Three molecular docking strategies dynamics simulation verify binding domains interacting AMK. Furthermore, anti-AD effects validated in zebrafish by testing behavior responses, apoptosis, deposition beta-amyloid (Aβ) brain. Ultimately, real-time qPCR targets, identified via multi-omics. Ferroptosis an important pathogenic mechanism AD, as suggested GSVA scores. may exert its activity through brain (ATP5MC3, GOT1, SAT1, EGFR, MAPK9) blood (G6PD, PGD, ALOX5, HMOX1, ULK1). EGFR HMOX1 further confirmed mediating TWAS, SMR, MR analyses. The GSEA results indicated that be involved oxidative phosphorylation-related pathways, while lysosome phagosome pathways. three simulations implied kinase domain catalytic played pivotal roles interaction targets. In model, AD-like symptoms including motor slowness delayed neuronal plaque brain, significantly improved after treatment. Accordingly, reversed abnormal expression egfra hmox1a, two core ferroptosis. alleviated modulation might reduce lipid peroxidation, thereby suppressing This provided evidence supporting therapeutic AMK-treated aid development interventions.

Language: Английский

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