Microglial activation states and their implications for Alzheimer's Disease

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: 12(1), P. 100013 - 100013

Published: Jan. 1, 2025

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the accumulation of toxic amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs) tau protein in brain. Microglia, key immune cells central nervous system, play an important role AD development progression, primarily through their responses to Aβ NFTs. Initially, microglia can clear Aβ, but AD, activation overwhelms protective mechanisms, leading sustained neuroinflammation that enhances plaque toxicity, setting off damaging cycle affects neurons, astrocytes, cerebral vasculature, other microglia. Current treatments have been largely ineffective, though emerging immunotherapies focusing on removal show promise, often overlook neuroinflammation. Activated display complex range phenotypes be broadly broken into pro- or anti-inflammatory states, although this dichotomy does not describe significant overlap between states. strongly induce inflammatory activity, triggering production reactive oxygen species, cytokines (e.g., TNF-α, IL-1β, IL-6), synapse engulfment, blood-brain barrier compromise, impaired clearance. These processes contribute neural tissue loss, manifesting as cognitive decline such executive function memory. Conversely, exerts neuroprotective effects suppressing pathways releasing neurotrophic factors aid neuron repair protection. Induction states may offer dual therapeutic approach address both AD. This suggests potential strategies modulate microglial phenotypes, aiming restore functions mitigate disease progression simultaneously targeting inflammation pathology.

Language: Английский

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Classifying Beta-Secretase 1 Inhibitor Activity for Alzheimer’s Drug Discovery with LightGBM

Journal of Computing Theories and Applications, Journal Year: 2024, Volume and Issue: 1(4), P. 358 - 367

Published: March 10, 2024

This study explores the utilization of LightGBM, a gradient-boosting framework, to classify inhibitory activity beta-secretase 1 inhibitors, addressing challenges Alzheimer's disease drug discovery. The aims enhance classification performance by focusing on overcoming limitations traditional statistical models and conventional machine-learning techniques in handling complex molecular datasets. By sourcing dataset 7298 compounds from ChEMBL database calculating descriptors for each compound as features, we employed LightGBM conjunction with set carefully selected achieve nuanced analysis activities. model's efficiency was benchmarked against algorithms, revealing LightGBM's superior accuracy (84.93%), precision (87.14%), sensitivity (89.93%), specificity (77.63%), F1-score (88.17%) classifying inhibitor activity. underscores critical role understanding efficacy, highlighting potential streamlining virtual screening process. Conclusively, findings advocate adoption computational discovery, offering promising avenue advancing therapeutic development facilitating identification candidates enhanced reliability.

Language: Английский

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The Role of Sirtuin 1 in Ageing and Neurodegenerative Disease: A Molecular Perspective

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 102, P. 102545 - 102545

Published: Oct. 17, 2024

Language: Английский

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Neurodegenerative Disease: From Molecular Basis to Therapy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 967 - 967

Published: Jan. 12, 2024

Neurodegenerative diseases are a heterogeneous group of age-related disorders characterised by the progressive degeneration or death neurons in central peripheral nervous system [...].

Language: Английский

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Quercetin ameliorates neuroinflammatory and neurodegenerative biomarkers in the brain and improves neurobehavioral parameters in a repeated intranasal amyloid-beta exposed model of Alzheimer's disease

Food & Function, Journal Year: 2024, Volume and Issue: 15(17), P. 8712 - 8728

Published: Jan. 1, 2024

Quercetin exerted antioxidant and anti-inflammatory properties to protect brain neuronal health. It also ameliorated Aβ deposition, regulated APP, BACE-1 tau hyperphosphorylation in brain, improved neurobehavioral cognitive parameters.

Language: Английский

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Palmitoylation-related gene ZDHHC22 as a potential diagnostic and immunomodulatory target in Alzheimer’s disease: insights from machine learning analyses and WGCNA

European journal of medical research, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 22, 2025

The mechanism of palmitoylation in the pathogenesis Alzheimer's disease (AD) remains unclear. This study retrieved AD data sets from GEO database to identify palmitoylation-associated genes (PRGs). applied WGCNA along with three machine learning algorithms—random forest, LASSO regression, and SVM–RFE—to further select key PRGs (KPRGs). diagnostic performance KPRGs was evaluated using Receiver Operating Characteristic (ROC) curve analysis. Immune cell infiltration analysis conducted assess correlations between immune types, a competing endogenous RNA (ceRNA) regulatory network constructed explore their potential mechanisms. 17 were identified sets, 7 showing increased expression 10 decreased expression. Through analyses, ZDHHC22 selected as KPRG. ROC demonstrated that had an area under value 0.659, indicating moderate potential. revealed significant associations several including naïve B cells, CD8 + T M1 macrophages. In addition, 25 miRNAs 55 lncRNAs predicted potentially target ZDHHC22, forming basis for lncRNA–miRNA–mRNA ceRNA network. is first use bioinformatics methods KPRG AD, highlighting its role diagnosis regulation. provides new insights into molecular mechanisms lays foundation future targeted therapeutic strategies.

Language: Английский

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Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer’s, Parkinson’s, and ALS

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12613 - 12613

Published: Nov. 24, 2024

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene these once-intractable conditions. This review synthesizes the latest insights into underlying dynamics neurodegeneration, revealing how intertwined pathways drive course diseases. With an eye on most promising advances, we explore innovative therapies emerging cutting-edge research: nanotechnology-based drug delivery systems capable navigating blood-brain barrier, gene-editing tools like CRISPR designed correct harmful variants, stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored align individual profiles, while diagnostics biomarkers ushering era early, precise disease detection. Furthermore, novel perspectives gut-brain axis sparking interest mounting evidence suggests microbiome modulation may play role reducing neuroinflammatory responses linked neurodegenerative progression. Taken together, advances signal shift toward comprehensive, personalized approach could transform care. By integrating techniques, this offers forward-looking perspective future where treatments aim just manage symptoms fundamentally alter progression, presenting renewed hope for improved patient outcomes.

Language: Английский

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Impact of GSK-3β and CK-1δ on Wnt signaling pathway in alzheimer disease: A dual target approach

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107378 - 107378

Published: April 17, 2024

Language: Английский

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Organophosphate Insecticide Malathion Induces Alzheimer’s Disease-Like Cognitive Impairment in Mice: Evidence of the Microbiota-Gut-Brain Axis

Environmental Science & Technology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 15, 2024

Evidence suggests that exposure to organophosphate pesticides increases the risk of neurodegenerative diseases, but mechanisms remain unclear. This study investigated effects malathion on Alzheimer's disease (AD)-like symptoms at environmentally relevant concentrations using wild-type (WT) and APP/PS1 transgenic mouse models. Results showed induced AD-like cognitive impairment, amyloid-β (Aβ) accumulation, neuroinflammation in WT mice, with worsened mice. Mechanistic studies revealed gut microbiota dysbiosis (reduced Lactobacillus Akkermansia, increased Dubosiella), causing barrier impairment tryptophan metabolism disruptions. resulted a significant increase indole derivatives activation colonic aryl hydrocarbon receptor (AhR), promoting kynurenine (KYN) pathway while inhibiting serotonin (5-HT) pathway. Increased neurotoxic KYN metabolites (3-hydroxykynurenine quinolinic acid) triggered systemic inflammation, upregulating hippocampal IL-6 IL-1β mRNA levels thereby neuroinflammation. Gut disruptions caused neurotransmitter imbalances, reducing 5-HT its derivatives. These promoted AD progression both highlights crucial role microbiota-gut-brain axis by exposure, providing insights into risks posed pesticides.

Language: Английский

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Mechanisms of mitophagy and oxidative stress in cerebral ischemia–reperfusion, vascular dementia, and Alzheimer’s disease

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Aug. 7, 2024

Neurological diseases have consistently represented a significant challenge in both clinical treatment and scientific research. As research has progressed, the significance of mitochondria pathogenesis progression neurological become increasingly prominent. Mitochondria serve not only as source energy, but also regulators cellular growth death. Both oxidative stress mitophagy are intimately associated with mitochondria, there is mounting evidence that exert pivotal regulatory influence on diseases. In recent years, been notable rise prevalence cerebral ischemia/reperfusion injury (CI/RI), vascular dementia (VaD), Alzheimer’s disease (AD), which collectively represent public health concern. Reduced levels observed CI/RI, VaD AD. The improvement pathology demonstrated through increase levels. CI/RI results tissue ischemia hypoxia, causes stress, disruption blood–brain barrier (BBB) damage to vasculature. BBB may induce or exacerbate some extent. addition, inadequate perfusion due altered function accumulation amyloid β (Aβ) thereby contributing exacerbating AD pathology. Intravenous plasminogen activator (tPA; alteplase) endovascular thrombectomy effective treatments for stroke. However, narrow window opportunity administration tPA thrombectomy, markedly elevated incidence disability among patients CI/RI. It regrettable currently no still specific drugs Despite availability U.S. Food Drug Administration (FDA)-approved first-line AD, including memantine, donepezil hydrochloride, galantamine, these agents do fundamentally block pathological process this paper, we undertake review mechanisms disorders, summary trials conducted proposal new strategy targeted disorders based stress.

Language: Английский

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