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

Article type: Research Article

Authors: Castillo, Carolina^a | Bravo-Arrepol, Gastón^b | Wendt, Aline^a | Saez-Orellana, Francisco^a | Millar, Camila^c | Burgos, Carlos F.^c | Gavilán, Javiera^a | Pacheco, Carla^d | Ahumada-Rudolph, Ramón^e | Napiórkowska, Mariola^f | Pérez, Claudia^{g; b} | Becerra, José^{g; b} | Fuentealba, Jorge^{a; *} | Cabrera-Pardo, Jaime R.^{e; *}

Affiliations: [a] Laboratory of Screening of Neuroactive Compounds, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepcion, Chile | [b] Unidad de Desarrollo Tecnológico, Parque Industrial Coronel, Universidad de Concepción, Concepción, Chile | [c] Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile | [d] Departamento de Bioquímica Clínica, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile | [e] Laboratorio de Química Aplicada y Sustentable (LabQAS), Departamento de Química, Universidad del Bio Bio, Concepción, Chile | [f] Chair and Department of Biochemistry, Medical University of Warsaw, Warsaw, Poland | [g] Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción, Chile

Correspondence: [*] Correspondence to: Jaime R. Cabrera-Pardo, PhD, Laboratorio de Química Aplicada y Sustentable (LabQAS), Departamento de Química, Universidad del Bio Bio, Concepción, Chile. E-mail: [email protected] and Jorge Fuentealba, Ph.D. Laboratory of Screening of Neuroactive Compounds, Departamento de Fisiología, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepcion, Chile. E-mail: [email protected].

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.

Keywords: Aβ interaction, Alzheimer’s disease, amyloid-β peptide, eudesmin, neuroprotection

DOI: 10.3233/JAD-220935

Journal: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022