Dataset Information

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity.

ABSTRACT:

Background

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects.

Objective

In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed.

Methods

Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs.

Results

In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu.

Conclusion

We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents.

SUBMITTER: Castillo C

PROVIDER: S-EPMC10473145 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity.

Castillo Carolina C Bravo-Arrepol Gastón G Wendt Aline A Saez-Orellana Francisco F Millar Camila C Burgos Carlos F CF Gavilán Javiera J Pacheco Carla C Ahumada-Rudolph Ramón R Napiórkowska Mariola M Pérez Claudia C Becerra José J Fuentealba Jorge J Cabrera-Pardo Jaime R JR

Journal of Alzheimer's disease : JAD 20230101 s1

<h4>Background</h4>Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on s ...[more]

PMID: 36463456

Similar Datasets

Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-β peptide (Aβ). Monomeric soluble Aβ can switch from helicoidal to β-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. Aβ can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that Aβ nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an Aβ analog containing a single residue (H to E) replacement that mimics the behavior of nitrated Aβ related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated Aβ oligomers was observed. Our results show that Aβ nitrotyrosination is a post-translational modification that increases Aβ synaptotoxicity.Significance statementWe report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-β (Aβ) favors the stabilization of highly toxic oligomers and inhibits the formation of Aβ fibrils. The nitrated Aβ oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Dataset Information

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity.

Background

Objective

Methods

Results

Conclusion

Publications

Neuroprotective Properties of Eudesmin on a Cellular Model of Amyloid-β Peptide Toxicity.

Similar Datasets

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