Review on anti-alzheimer drug development: approaches, challenges and perspectives

RSC Advances, Год журнала: 2024, Номер 14(16), С. 11057 - 11088

Опубликована: Янв. 1, 2024

Alzheimer has many crucial factors that should be considered in order to get better results from clinical trials. Benzimidazole and its isosteres represent significant scaffolds for designing potential multi-target anti-alzheimer molecules.

Язык: Английский

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Chronic Postsurgical Pain Raises Risk of Dementia

European Journal of Pain, Год журнала: 2025, Номер 29(4)

Опубликована: Фев. 21, 2025

ABSTRACT Purpose This study aimed to investigate the association between chronic postsurgical pain (CPSP) and risk of dementia, addressing a significant gap in existing literature highlighting potential implications for clinical practice public health. Patients Methods Utilising data from Taiwan's National Health Insurance Research Database, propensity score‐matched cohort was conducted involving 142,682 patients who underwent major surgery 2004 2018. CPSP defined as prolonged analgesic use post‐surgery, dementia diagnosis tracked until December 31, 2022. Multivariable Cox regression models were employed calculate adjusted hazard ratios (aHRs) versus non‐CPSP groups. Results Before score matching, ( n = 37,438) exhibited higher with aHRs 1.35 (95% CI: 1.30–1.40). After aHR remained elevated at 1.31 1.26–1.37), indicating risk. Subgroup analysis confirmed this across various demographic factors, sensitivity reinforcing robustness findings. Conclusion establishes an independent predictor risk, importance postoperative management mitigating long‐term cognitive outcomes. Approximately 30% post‐CPSP presents opportunity reduction through effective strategies, emphasising need targeted interventions address critical healthcare issue. Significance provides compelling evidence that significantly increases previously underexplored connection decline. By establishing our findings underscore strategies surgical patients, particularly mitigate heightened improve

Язык: Английский

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Integrated Multi-Omics Analyses of Synaptosomes Revealed Synapse-Centered Novel Targets in Alzheimer's Disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Synapse dysfunction is an early event in Alzheimer's disease (AD) caused by various factors such as Amyloid beta, p-tau, inflammation, and aging. However, the exact molecular mechanism of synapse AD largely unknown. To understand this, we comprehensively analyzed synaptosome fraction postmortem brain samples from patients cognitively normal individuals. We conducted high-throughput transcriptomic analyses to identify changes microRNA (miRNA) mRNA levels synaptosomes extracted brains both unaffected individuals those with (AD). Additionally, performed mass spectrometry analysis synaptosomal proteins same sample group. These revealed significant differences miRNAs, mRNAs, between groups. further pathways or molecules involved, used integrated omics approach studied interactions deregulated control group, which demonstrated impact miRNAs on their target mRNAs proteins. Furthermore, DIABLO highlighted complex relationships that could be key understanding pathophysiology AD. Our study identified synapse-centered novel candidates critical restoring

Язык: Английский

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Application of Nanobiosensor Engineering in the Diagnosis of Neurodegenerative Disorders

Results in Engineering, Год журнала: 2024, Номер 24, С. 102790 - 102790

Опубликована: Сен. 5, 2024

Язык: Английский

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Polar lipids modify Alzheimer’s Disease pathology by reducing astrocyte pro-inflammatory signaling through platelet-activating factor receptor (PTAFR) modulation

Lipids in Health and Disease, Год журнала: 2024, Номер 23(1)

Опубликована: Апрель 20, 2024

Abstract Background Pro-inflammatory processes triggered by the accumulation of extracellular amyloid beta (Aβ) peptides are a well-described pathology in Alzheimer's disease (AD). Activated astrocytes surrounding Aβ plaques contribute to inflammation secreting proinflammatory factors. While may phagocytize and clearance, reactive also increase production. Therefore, identifying factors that can attenuate astrocyte activation neuroinflammation how these influence pro-inflammatory pathways is important for developing therapeutic preventive strategies AD. Here, we identify platelet-activating factor receptor (PTAFR) pathway as key mediator activation. Intriguingly, several polar lipids (PLs) have exhibited anti-inflammatory protective properties outside central nervous system through their inhibitory effect on PTAFR pathway. Thus, additionally investigated whether different PLs exert effects PAF presence influences astrocytic signaling known AD pathologies vitro. Methods from salmon yogurt were extracted using novel food-grade techniques fatty acid profile was determined LC/MS. The parameters such generation oxygen species (ROS) assessed. Additionally, secretome treated with aged neurons measured. Results We show obtained lower activation, (ROS), accumulation. Cell health exposed salmon-derived less affected than those only. Conclusion Our results highlight underlying mechanism, why consuming PL-rich foods fish dairy reduce risk dementia associated disorders.

Язык: Английский

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Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer’s disease

Scientific Reports, Год журнала: 2023, Номер 13(1)

Опубликована: Авг. 24, 2023

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of Aβ plaques and neurofibrillary tangles, resulting in synaptic loss neurodegeneration. The retina an extension central nervous system within eye, sharing many structural similarities with brain, previous studies have observed AD-related phenotypes retina. Three-dimensional retinal organoids differentiated from human pluripotent stem cells (hPSCs) can effectively model some earliest manifestations states, yet early AD-associated not been examined. Thus, current study focused upon differentiation hPSCs into for analysis alterations. Results demonstrated robust both familial AD unaffected control cell lines, exhibiting significant increase Aβ42:Aβ40 ratio as well phosphorylated Tau protein, characteristic pathology. Further, transcriptional analyses differential expression genes cellular pathways, including those associated dysfunction. Taken together, demonstrates ability to serve powerful identification alterations AD.

Язык: Английский

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AAGGG repeat expansions trigger RFC1 -independent synaptic dysregulation in human CANVAS neurons

Science Advances, Год журнала: 2024, Номер 10(36)

Опубликована: Сен. 4, 2024

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited neurodegenerative disorder caused by intronic biallelic, nonreference CCCTT/AAGGG repeat expansions within RFC1 . To investigate how these repeats cause disease, we generated patient induced pluripotent stem cell–derived neurons (iNeurons). do not alter neuronal splicing, expression, or DNA repair pathway function. In reporter assays, AAGGG are translated into pentapeptide proteins. However, proteins RNA foci were detected in iNeurons, overexpression of failed to induce toxicity. CANVAS iNeurons exhibit defects development diminished synaptic connectivity that rescued CRISPR deletion single expanded allele. These deficits neither replicated knockdown control nor reprovision iNeurons. findings support repeat-dependent but protein–independent dysfunction CANVAS, implications for therapeutic this currently untreatable condition.

Язык: Английский

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Emerging biophysical techniques for probing synaptic transmission in neurodegenerative disorders

Neuroscience, Год журнала: 2024, Номер 565, С. 63 - 79

Опубликована: Ноя. 26, 2024

Язык: Английский

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A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(7), С. 4434 - 4460

Опубликована: Май 23, 2024

Abstract INTRODUCTION Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, dysfunction. METHODS PTX‐BD10‐2 (BD10‐2), a small molecule partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APP L/S ) wild‐type controls. Effects on hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, RNA sequencing. RESULTS In APP mice, BD10‐2 treatment improved LTP deficits. This accompanied normalized phosphorylation of protein (Akt), calcium‐calmodulin–dependent II (CaMKII), AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment proteins; increased excitatory synapse number. also had potentially favorable effects LTP‐dependent complement pathway gene transcription. DISCUSSION prevented /Aβ‐associated deficits, reduced abnormalities in synapse‐related transcription genes, bolstered transcriptional changes associated microglial immune response. Highlights Small modulation tropomyosin restores behavior an (AD) model. Modulation TrkB TrkC regulates are candidate targets for translational therapeutics. Electrophysiology combined transcriptomics elucidates restoration. identifies neuron microglia AD‐relevant human‐mouse co‐expression modules.

Язык: Английский

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Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

Pharmaceuticals, Год журнала: 2024, Номер 17(6), С. 788 - 788

Опубликована: Июнь 16, 2024

The COVID-19 pandemic, caused by infection with the SARS-CoV-2 virus, is associated cognitive impairment and Alzheimer’s disease (AD) progression. Once it enters brain, virus stimulates accumulation of amyloids in brain that are highly toxic to neural cells. These may trigger neurological symptoms COVID-19. meningeal lymphatic vessels (MLVs) play an important role removal toxins mediate viral drainage from brain. MLVs considered a promising target prevent COVID-19-exacerbated dementia. However, there limited methods for augmentation MLV function. This review highlights new discoveries field COVID-19-mediated amyloid development strategies stimulate clearance through other pathways. based on innovative treating dysfunction induced infection, including use photobiomodulation, plasmalogens, medicinal herbs, which offer hope addressing challenges posed virus.

Язык: Английский

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