Extracellular Vesicles, Cell-Penetrating Peptides and miRNAs as Future Novel Therapeutic Interventions for Parkinson’s and Alzheimer’s Disease

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 728 - 728

Published: Feb. 28, 2023

Neurodegeneration is hallmarked by the progressive loss of dopaminergic neurons and/or a significant increase in protein aggregates brain. Neurodegenerative diseases are leading cause death worldwide with over 15 million people currently suffering from either Parkinson’s disease (PD) or Alzheimer’s (AD). PD often characterized both motor and non-motor symptoms, including muscle rigidity, tremors bradykinesia, AD displaying symptoms confusion dementia. The current mainstay therapeutics includes pharmacological approaches such as levodopa to replace dopamine patients, deep brain stimulation affected regions physical therapy. However, these treatments typically not disease-modifying, though they do help at least for some time symptom management. These also fail due their inability cross blood–brain barrier. There need develop new strategies target neurodegeneration an ever-ageing population. First, we review limitations. Second, use extracellular vesicles (EVs), cell-penetrating peptides (CPPs) miRNAs neuroprotective agents. Finally, discuss possibility exploiting combinatory therapeutic, alongside potential drawbacks.

Language: Английский

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Polyamine Dysregulation and Nucleolar Disruption in Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 98(3), P. 837 - 857

Published: March 12, 2024

A hypothesis of Alzheimer’s disease etiology is proposed describing how cellular stress induces excessive polyamine synthesis and recycling which can disrupt nucleoli. Polyamines are essential in nucleolar functions, such as RNA folding ribonucleoprotein assembly. Changes the pool anionic cationic polyamines acting counterions cause significant dynamics. Polyamine reduces S-adenosylmethionine which, at low levels, triggers tau phosphorylation. Also, acetyl-CoA needed for acetylcholine, disease. Extraordinary expansion and/or contraction epigenetic control peri-nucleolar chromatin, chromosome 14 with presenilin-1 gene; 21 amyloid precursor protein 17 19 APOE4 inactive X (Xi; aka “nucleolar satellite”) normally silent spermine synthase (polyamine synthesis) spermidine/spermine-N1-acetyltransferase recycling) alleles. Chromosomes 17, Xi have high concentrations Alu elements be transcribed by polymerase III if positioned nucleosomes displaced from elements. sudden flood transcripts competitively bind nucleolin usually bound to sequences structural RNAs that stabilize heterochromatic shell. This competition leads loss integrity leaking aggregation phosphorylated tau. The was developed key word searches (e.g., PubMed) using relevant terms Alzheimer’s, lupus, nucleolin) based on a systems biology approach exploring autoimmune tautology, gaining synergistic insights other diseases.

Language: Английский

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Developing Non-Invasive Molecular Markers for Early Risk Assessment of Alzheimer's Disease

Biomarkers in Neuropsychiatry, Journal Year: 2025, Volume and Issue: unknown, P. 100120 - 100120

Published: Jan. 1, 2025

Language: Английский

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Massive changes in gene expression and their cause(s) can be a unifying principle in the pathobiology of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract Understanding of the biology Alzheimer's disease (AD) has long been fragmented, with various investigators concentrating on amyloid beta (Aβ) or tau, inflammation, cell death pathways, misfolded proteins, glia, and more. Yet data from multiple authors repeatedly shown altered expression myriad genes related to these seemingly disparate phenomena. In 2022, Morgan et al. organized massive changes in AD a meticulous survey literature Kyoto Encyclopedia Genes Genomes (KEGG) pathways. Their showed that 91% known KEGG pathways are involved many represented by cellular/molecular phenomena AD. Such then raise fundamental question: What mechanism(s) may be responsible for such widespread gene expression? We review evidence unifying model based sequestrations stress granules alteration nucleocytoplasmic transport Highlights (AD), critical take place neurons before appearance plaques tangles. Addressing early provides path detection effective intervention

Language: Английский

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Pathway-based network medicine identifies novel natural products for Alzheimer’s disease

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 14, 2025

Alzheimer's disease (AD) is the leading cause of dementia, characterized by a complex pathogenesis that complicates development effective treatments. Natural products are promising multitarget agents because their ability to interact with multiple molecular targets. Network-based medicine presents robust strategy for discovering such agents, which can address intricate mechanisms underlying AD. In this study, we constructed an AD-related pathway-gene network via text mining and pathway database construction. This facilitated identification natural target pathways genes associated We evaluated safety profiles two selected in C57BL/6J mice through assessments general behavior, body weight changes, vital organ morphology, hematological biochemical parameters. APP/PS1 transgenic were subsequently treated these products—either individually or combination—to assess therapeutic effects. Cognitive function was behavioral tests, as novel object recognition, Y-maze, Morris water maze tests. Additionally, immunohistochemical staining enzyme-linked immunosorbent assays performed examine Aβ-associated pathological changes. Transcriptomic analysis quantitative real-time polymerase chain reaction (qRT-PCR) employed elucidate effects products. The encompassed three perspectives: (i) Most Studied Pathways (21 5325 genes), (ii) Gene-Associated (26 2557 (iii) Popular (24 3435 genes). Two products, (-)-Vestitol Salviolone, further validation. Their confirmed mice. Notably, combination Salviolone synergistically affected cognitive reducing Aβ deposition lowering toxic soluble levels brain. qRT-PCR experiments revealed regulated more comprehensively, particularly affecting Neuroactive ligand-receptor interaction Calcium signaling pathway. Our findings demonstrate screening potential therapeutics candidates AD treatment underscored synergistic effects, attributed comprehensive regulation AD-associated genes.

Language: Английский

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Comparison of Deep Learning and Traditional Machine Learning Models for Predicting Mild Cognitive Impairment Using Plasma Proteomic Biomarkers

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2428 - 2428

Published: March 8, 2025

Mild cognitive impairment (MCI) is a clinical condition characterized by decline in ability and progression of impairment. It often considered transitional stage between normal aging Alzheimer’s disease (AD). This study aimed to compare deep learning (DL) traditional machine (ML) methods predicting MCI using plasma proteomic biomarkers. A total 239 adults were selected from the Disease Neuroimaging Initiative (ADNI) cohort along with pool 146 We evaluated seven ML models (support vector machines (SVMs), logistic regression (LR), naïve Bayes (NB), random forest (RF), k-nearest neighbor (KNN), gradient boosting (GBM), extreme (XGBoost)) six variations neural network (DNN) model—the DL model H2O package. Least Absolute Shrinkage Selection Operator (LASSO) 35 biomarkers pool. Based on grid search, DNN an activation function “Rectifier With Dropout” 2 layers 32 revealed best highest accuracy 0.995 F1 Score 0.996, while among methods, XGBoost was 0.986 0.985. Several correlated APOE-ε4 genotype, polygenic hazard score (PHS), three cerebrospinal fluid (Aβ42, tTau, pTau). Bioinformatics analysis Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) several molecular functions pathways associated biomarkers, including cytokine-cytokine receptor interaction, cholesterol metabolism, regulation lipid localization. The results showed that may represent promising tool prediction MCI. These help early diagnosis, prognostic risk stratification, treatment interventions for individuals at

Language: Английский

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Identification of Therapeutic Potential of Hydroxychavicol Against Alzheimer’s Disease: An Integrated Network Pharmacology, Molecular Docking, and Dynamic Simulation Study

Journal of Aging Research, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

Alzheimer's disease (AD) is a commonly occurring neurodegenerative in elderly and it leading cause of dementia worldwide. Hydroxychavicol (HC), major phenolic component Piper betle, has prominent anti-inflammatory antioxidant properties, studies have found its role cognition improvement. Here systematic approach to deciphering the potential protein targets HC AD through network pharmacology validation from molecular docking dynamics simulation study. First, druglikeliness was predicted using SwissADME analysis, which showed significant druglikeliness. A total 88 possible target genes between were obtained Swiss Target Prediction, HIT Version 2, DisGeNET, GeneCards database. The pathway analysis carried out STRING database several including COMT, HSP90AA1, GAPDH as top hub on basis degree. GO KEGG analyses demonstrated that core mainly involved cAMP, PI3K/AkT, HIF1, Rap1, Calcium signaling pathways. with resulted highest binding COMT (-8.9 kcal/mol), (-6.7 HSP90AA1 (-6.5 kcal/mol) stable regulates dopamine levels prefrontal cortex impairment associated rapid progression AD. HSP90, ubiquitous chaperone, regulating tau metabolism Aβ processing be downregulated been reported disease-susceptible gene interaction amyloid precursor NFTs also reported. These findings suggest promising therapeutic candidate, targeting multiple AD-related pathways, warranting further investigation into mechanisms for clinical application.

Language: Английский

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Role of non‑coding RNAs as biomarkers and the application of omics technologies in Alzheimer's disease (Review)

International Journal of Molecular Medicine, Journal Year: 2022, Volume and Issue: 51(1)

Published: Nov. 24, 2022

Alzheimer's disease (AD) is a neurodegenerative disorder that has significant association with age. Despite its increasing incidence in the population, etiology of remains poorly understood, and there are currently no effective treatments readily available. The main genes associated AD amyloid precursor protein, presenilin‑1 presenilin‑2, as well apolipoprotein E gene. In addition to genetic factors, wide range environmental lifestyle factors equally characterized risk for development AD, while non‑coding RNAs (ncRNAs) other epigenetic mechanisms play key role their detrimental effects. Multiple types ncRNAs, such microRNAs, circular RNAs, Piwi‑interacting long being increasingly implicated AD. Alterations ncRNAs can be detected cerebrospinal fluid, brain, highlighting these promising biomarkers detection treatment Developments high‑throughput technologies have led so‑called 'omics' era, which involves collection big data information at both molecular protein levels, combining novel computational statistical tools capable analyzing filtering data. present review discusses use summarizes findings from application omics

Language: Английский

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The Caribbean-Hispanic Alzheimer's disease brain transcriptome reveals ancestry-specific disease mechanisms

Neurobiology of Disease, Journal Year: 2022, Volume and Issue: 176, P. 105938 - 105938

Published: Nov. 30, 2022

Identifying ancestry-specific molecular profiles of late-onset Alzheimer's Disease (LOAD) in brain tissue is crucial to understand novel mechanisms and develop effective interventions non-European, high-risk populations. We performed gene differential expression (DE) consensus network-based analyses RNA-sequencing data postmortem from 39 Caribbean Hispanics (CH). To identify ancestry-concordant -discordant profiles, we compared our results those two independent non-Hispanic White (NHW) samples (n = 731). In CH, identified 2802 significant DE genes, including several LOAD known-loci. effects were highly concordant across ethnicities, with 373 genes transcriptome-wide all three cohorts. Cross-ancestry meta-analysis found NPNT be the top gene. replicated over 82% meta-analyses genome-wide signals single-nucleus RNA-seq (including known-genes SORL1, FBXL7, CLU, ABCA7). Increasing representation genetic studies will allow for deeper understanding improving precision treatment options understudied groups.

Language: Английский

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In-vivo neuronal dysfunction by Aβ and tau overlaps with brain-wide inflammatory mechanisms in Alzheimer’s disease

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: June 19, 2024

The molecular mechanisms underlying neuronal dysfunction in Alzheimer’s disease (AD) remain uncharacterized. Here, we identify genes, pathways and cellular components associated with whole-brain dysregulation caused by amyloid-beta (Aβ) tau deposits the living human brain. We obtained in-vivo resting-state functional MRI (rs-fMRI), Aβ- tau-PET for 47 cognitively unimpaired 16 AD participants from Translational Biomarkers Aging Dementia cohort. Adverse activity impacts Aβ were quantified personalized dynamical models fitting pathology-mediated computational signals to participant’s real rs-fMRIs. Then, detected robust brain-wide associations between spatial profiles of Aβ-tau gene expression neurotypical transcriptome (Allen Human Brain Atlas). Within distinctive signature dysfunction, several genes have prominent roles microglial activation interactions tau. Moreover, vulnerability estimations revealed strong association patterns tau’s synergistic impact on ( q < 0.001). These results further support central role immune system neuroinflammatory pathogenesis. Neuronal pathologies also synaptic developmental processes. In addition, identified drug candidates vast LINCS library halt or reduce observed effects activity. Top-ranked pharmacological interventions target inflammatory, cancer cardiovascular pathways, including specific medications undergoing clinical evaluation AD. Our findings, based examination molecular-pathological-functional humans, may accelerate process bringing effective therapies into practice.

Language: Английский

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