Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

Journal of Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 74(3)

Published: July 3, 2024

Abstract Alzheimer’s disease (AD) is the most prevalent neurodegenerative worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism dysregulated iron homeostasis have been implicated in pathogenesis of this disorder, but detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) lipid-binding protein that occurs large quantities human blood plasma, polymorphism APOE gene locus identified as risk factors for AD. The genome involves three major alleles ( APOE2 , APOE3 APOE4 ), which encode subtly distinct apolipoprotein isoforms (APOE2, APOE3, APOE4). canonic function these apolipoproteins transport brain, allele carriers much higher In fact, about 60% clinically diagnosed AD patients carry at least one their genomes. Although key processes AD, such extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation neurofibrillary tangles, modified metabolism, ferroptotic cell death, underlying molecular are not well understood. As all mammalian cells, plays crucial role neuronal functions dysregulation also Imbalances impairment hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to ferroptosis. review, we summarize current knowledge on -related potential ferroptosis Pharmacological interference with might offer innovative strategies therapeutic interventions.

Language: Английский

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Alzheimer’s Disease: Exploring Pathophysiological Hypotheses and the Role of Machine Learning in Drug Discovery

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1004 - 1004

Published: Jan. 24, 2025

Alzheimer’s disease (AD) is a major neurodegenerative dementia, with its complex pathophysiology challenging current treatments. Recent advancements have shifted the focus from traditionally dominant amyloid hypothesis toward multifactorial understanding of disease. Emerging evidence suggests that while amyloid-beta (Aβ) accumulation central to AD, it may not be primary driver but rather part broader pathogenic process. Novel hypotheses been proposed, including role tau protein abnormalities, mitochondrial dysfunction, and chronic neuroinflammation. Additionally, gut–brain axis epigenetic modifications gained attention as potential contributors AD progression. The limitations existing therapies underscore need for innovative strategies. This study explores integration machine learning (ML) in drug discovery accelerate identification novel targets candidates. ML offers ability navigate AD’s complexity, enabling rapid analysis extensive datasets optimizing clinical trial design. synergy between these themes presents promising future more effective

Language: Английский

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Gallic acid enhances memory, learning and reduces neuroinflammation in a rat model of scopolamine-induced cholinergic dysfunction

Inflammopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 16, 2025

Language: Английский

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Deep joint learning diagnosis of Alzheimer’s disease based on multimodal feature fusion

BioData Mining, Journal Year: 2024, Volume and Issue: 17(1)

Published: Nov. 5, 2024

Alzheimer's disease (AD) is an advanced and incurable neurodegenerative disease. Genetic variations are intrinsic etiological factors contributing to the abnormal expression of brain function structure in AD patients. A new multimodal feature fusion called "magnetic resonance imaging (MRI)-p value" was proposed construct 3D images by introducing genes as a priori knowledge. Moreover, deep joint learning diagnostic model constructed fully learn features. One branch trained residual network (ResNet) features local pathological regions. The other learned position information regions with different changes categories subjects' brains attention convolution, then obtained discriminative probability from locations via convolution global average pooling. two branches were linearly interacted acquire basis for classifying subjects. diagnoses health control (HC), mild cognitive impairment (MCI), HC MCI performed data Disease Neuroimaging Initiative (ADNI). results showed that method achieved optimal AD-related diagnosis. classification accuracy (ACC) area under curve (AUC) three experimental groups 93.44% 96.67%, 89.06% 92%, 84% 81.84%, respectively. total six novel found be significantly associated AD, namely NTM, MAML2, NAALADL2, FHIT, TMEM132D PCSK5, which provided targets potential treatment diseases.

Language: Английский

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Voluntary wheel running decreases amyloidogenic pathway and rescues cognition and mitochondrial energy metabolism in middle-aged female 3xTg-AD mouse model of Alzheimer's disease

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 102(2), P. 424 - 436

Published: Oct. 29, 2024

Evidence supports the neuroprotective effects of physical activity, either in experimental animal models or humans. However, biological mechanisms by which exercise modulates dementia and Alzheimer's disease (AD) progression are still unclear.

Language: Английский

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Evaluating the bi-directional causal association between temporomandibular disorders and neurodegenerative diseases: a two-sample Mendelian randomisation study

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

Published: March 26, 2024

Background Previous observational studies suggested that temporomandibular disorders (TMD) are associated with neurodegenerative diseases (NDs). This association may be mediated by confounding factors or reverse causation. Therefore, the objective of this study was to test causal relationship between TMD and four most common NDs [Alzheimer's disease (AD), Parkinson's (PD), Amyotrophic Lateral Sclerosis (ALS) Multiple (MS)]. Methods Data on (N = 134,280), AD 63,926), PD 482,730), ALS 80,610), MS 115,803) were extracted from publicly available Genome-Wide Association Studies (GWAS). Single-nucleotide polymorphisms (SNPs) used as instrumental variables (IVs) screened setting strength eliminating linkage disequilibrium. Inverse-variance weighting (IVW) method employed primary analytical approach. However, weighted median, Mendelian randomization-Egger, simple modes complementary analysis methods evaluate effects. Tests for heterogeneity pleiotropy also performed. The results' stability assessed using a leave-one-out analysis. Results Our findings revealed significant positive genetic correlations (odds ratio 1.223, 95% confidence interval 1.064–1.406, P 0.005). There no AD, ALS, MS. In randomisation, results supported effect (all > 0.05). analyses did not reveal any evidence horizontal pleiotropy. Conclusions These supply potential PD, emphasising importance effectively managing prevent PD. it is imperative conduct comprehensive validate elucidate underlying mechanisms association.

Language: Английский

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Exploring the potential mechanism of Polygonatum sibiricum for Alzheimer's disease based on network pharmacology and molecular docking

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

Published: April 17, 2024

Abstract Alzheimer's disease (AD) is a neurodegenerative disease, and there have been no systematic studies of Polygonatum against disease. This study aimed to identify the primary active components potential mechanisms action in treatment AD through network pharmacology molecular docking. Polygonatum's ingredients corresponding targets were identified using Traditional Chinese Medicine Systematic Pharmacology Database Analysis Platform (TCMSP). Disease retrieved from therapeutic target database (TTD), Online Mendelian Inheritance Man(OMIM), GeneCards, Disgenet databases. We constructed protein interaction PPI networks performed Gene Ontology (GO) functional enrichment analysis as well Kyoto Encyclopedia Genes Genomes (KEGG) pathway on common targets. As result, total 10 108 screened Polygonatum. After analysis, 29 genes core genes. According GO found be mainly involved signal transduction, positive regulation gene expression, so on. The KEGG revealed that signaling pathways comprised cancer, neurodegeneration - multiple diseases, PI3K-Akt pathway. docking results indicated ten exhibited strong binding affinity with six before. confirms involves multi-targets multi-pathway interactions, which provides new perspective offers theoretical basis for further research pathogenesis AD.

Language: Английский

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Exploring the potential mechanism of Polygonatum sibiricum for Alzheimer’s disease based on network pharmacology and molecular docking: An observational study

Medicine, Journal Year: 2024, Volume and Issue: 103(52), P. e40726 - e40726

Published: Dec. 27, 2024

Alzheimer's disease (AD) is a neurodegenerative disease, and there have been no systematic studies of Polygonatum against disease. Therefore, our study will elucidate the mechanism AD based on network pharmacology molecular docking. The active ingredients corresponding targets were identified using traditional Chinese medicine database analysis platform. Disease retrieved from therapeutic target database, Online Mendelian Inheritance in Man, GeneCards, Disgenet databases. Using STRING we constructed protein interaction networks performed gene ontology functional enrichment as well Kyoto encyclopedia genes genomes pathway common targets. We then drew drug-component-target-pathway-disease maps Cytoscape 3.10.1 software validated docking AutoDock4. A total 10 108 screened Polygonatum, 29 (including AKT1 STAT3) core genes. According to analysis, found be mainly involved signal transduction, positive regulation expression, negative apoptotic process, so on. revealed that signaling pathways comprised cancer, neurodegeneration - multiple diseases, PI3K-Akt pathway. results indicated exhibited strong binding affinity with 6 before. activity could attributed biological effects via multi-pathways (pathways pathway). activities estimated good level by These discoveries disclosed multi-component, multi-target, multi-pathway characteristics AD, providing new strategy for such medical problem.

Language: Английский

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