Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Language: Английский

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Microglia and Cholesterol Handling: Implications for Alzheimer’s Disease

Biomedicines, Journal Year: 2022, Volume and Issue: 10(12), P. 3105 - 3105

Published: Dec. 1, 2022

Cholesterol is essential for brain function and structure, however altered cholesterol metabolism transport are hallmarks of multiple neurodegenerative conditions, including Alzheimer’s disease (AD). The well-established link between apolipoprotein E (APOE) genotype increased AD risk highlights the importance lipid in etiology. Whereas more known about regulation dysregulation neurons astrocytes, less how microglia, immune cells brain, handle cholesterol, subsequent implications ability microglia to perform their functions. Evidence emerging that a high-cholesterol environment, particularly context defects (e.g., expression high-risk APOE4 isoform), can lead chronic activation, inflammatory signaling, reduced phagocytic capacity, which have been associated with pathology. In this narrative review we describe regulates phenotype function, discuss what effects statins on as well highlighting areas future research advance knowledge development novel therapies prevention treatment AD.

Language: Английский

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Intranasal amyloid model of Alzheimer’s disease - potential opportunities and challenges

Pharmacological Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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In Vivo Seeding of Amyloid-β Protein and Implications in Modeling Alzheimer’s Disease Pathology

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 571 - 571

Published: April 11, 2025

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular plaques containing amyloid β-protein (Aβ) and intracellular neurofibrillary tangles formed tau. Cerebral Aβ accumulation initiates noxious cascade that leads to irreversible neuronal degeneration memory impairment in older adults. Recent advances seeding studies offer promising avenue for exploring the mechanisms underlying deposition complex pathological features of AD. However, extent which inoculated seeds can induce reproducible reliable manifestations remains unclear due significant variability across studies. In this review, we will discuss several factors contribute induction or acceleration consequent pathologies. Specifically, focus on diversity host animals, sources recipe seeds, inoculating strategies. By integrating these key aspects, review aims comprehensive perspective AD provide guidance modeling pathogenesis through exogenous introduction seeds.

Language: Английский

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Linderae Radix Ameliorates Cognitive Dysfunction by Inhibiting Neuroinflammation and Synaptic Damage in Alzheimer’s Disease Models

Molecular Neurobiology, Journal Year: 2023, Volume and Issue: 60(12), P. 7196 - 7207

Published: Aug. 5, 2023

Language: Английский

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Inducing Agents for Alzheimer’s Disease in Animal Models

Journal of Exploratory Research in Pharmacology, Journal Year: 2024, Volume and Issue: 000(000), P. 000 - 000

Published: July 16, 2024

The most prevalent form of dementia, Alzheimer's disease (AD), is a neurological disorder that causes gradual memory loss. AD characterized by amyloid-beta plaques, neurofibrillary tangles, and neuron While preclinical clinical trials are underway to reduce the generation overall brain load, current treatment focuses on alleviating symptoms. Animal studies essential for advancing our understanding AD, identifying potential drug targets, testing experimental therapies. An ideal animal model not only exhibits same symptoms pathological changes as human but also follows sequence events. This review highlights various inducing agents used in animals, such streptozotocin, aluminium chloride, trimethyltin, lipopolysaccharide, scopolamine, others, along with their underlying mechanisms. outcomes some develop discussed briefly. Among chemically induced models, streptozotocin frequently used, while d-galactose, aluminium-induced models being because they non-invasive, reproducible, compatible. However, none chemical/drug-induced fully capture scope pathology cognitive impairment. Overall, further research necessary establish stability terms consistency reproducibility.

Language: Английский

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Synthetic, Cell-Derived, Brain-Derived, and Recombinant β-Amyloid: Modelling Alzheimer’s Disease for Research and Drug Development

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 15036 - 15036

Published: Nov. 30, 2022

Alzheimer's disease (AD) is the most common cause of dementia in elderly, characterised by accumulation senile plaques and tau tangles, neurodegeneration, neuroinflammation brain. The development AD a pathological cascade starting according to amyloid hypothesis with aggregation β-amyloid peptide (Aβ), which induces hyperphosphorylation promotes pro-inflammatory activation microglia leading synaptic loss and, ultimately, neuronal death. Modelling AD-related processes important for both studying molecular basis novel therapeutics. replication these often achieved use purified Aβ peptide. However, preparations obtained from different sources can have strikingly properties. This review aims compare structure biological effects oligomers aggregates higher order: synthetic, recombinant, cell culture, or extracted brain tissue. authors summarise applicability modelling aggregation, neurotoxicity, cytoskeleton damage, receptor toxicity vitro cerebral amyloidosis, plasticity disruption, cognitive impairment vivo ex vivo. Further, paper discusses causes reported differences effect mentioned above. points importance source could help researchers choose optimal way model Aβ-induced abnormalities.

Language: Английский

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Long-term exercise training inhibits inflammation by suppressing hippocampal NLRP3 in APP/PS1 mice

Sports Medicine and Health Science, Journal Year: 2023, Volume and Issue: 5(4), P. 329 - 335

Published: Sept. 22, 2023

Behavioral experiments have demonstrated that long-term physical exercise can be beneficial for learning and memory dysfunction caused by neuroinflammation in Alzheimer's disease (AD). However, the molecular mechanism remains poorly understood due to a lack of sufficient pertinent biochemical evidence. We investigated potential effect on cognition hippocampal gene protein expression changes transgenic AD mouse model. Following twenty weeks treadmill exercise, mice showed improvement cognitive functions downregulation Nod-like receptor 3 (NLRP3) (

Language: Английский

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Regional AT-8 reactive tau species correlate with intracellular Aβ levels in cases of low AD neuropathologic change

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: Feb. 14, 2024

Abstract The amyloid cascade hypothesis states that Aβ aggregates induce pathological changes in tau, leading to neurofibrillary tangles (NFTs) and cell death. A caveat with this is the spatio-temporal divide between plaques NFTs. This has been addressed by inclusion of soluble tau species revised hypothesis. Nevertheless, despite potential for non-plaque contribute pathology, few studies have examined relative correlative strengths total Aβ, plaque intracellular pathology within a single tissue cohort. Employing frozen fixed frontal cortex grey white matter from non-AD controls (Con; n = 39) Alzheimer’s disease (AD) cases ( 21), biochemical immunohistochemical (IHC) measures AT-8 phosphorylated were assessed. Biochemical native-state dot blots crude lysates demonstrated robust correlations when considered as combined cohort (Con AD) Con AD cases, separately. In contrast, no associations reported using IHC measurements either or cases. However, was measured via specific antibody MOAB-2, relationship but not Collectively data suggests accumulating may influence early AD-related neuropathological change. Despite lower levels phospho-tau controls, relationships observed suggest physiological association production phosphorylation, which be modified during disease. study supportive demonstrates regional associative extracellular plaques.

Language: Английский

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Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 611 - 611

Published: March 8, 2024

The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson’s (PD). Astemizole also interacts with an anomalous aggregation Alzheimer’s disease-related amyloid-β (Aβ) peptide and inhibitory activity on the human prion protein PrPSc. We hypothesized that proposed benefits PD can be associated attenuation pathological α-synuclein (α-syn) aggregation. tested fibrillation processes amyloid peptides using thioflavin T monitoring, Congo red spectral analysis, cell viability study, transmission electron microscopic imaging. found did not inhibit α-syn vitro even at a high molar ratio but inhibited assembly Aβ aggregates. Our results suggest effect formation is target-protein selective, beneficial this compound observed translational might due to its ameliorating

Language: Английский

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