Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons

Article type: Research Article

Authors: Zolezzi, Juan M.^{a; e} | Lindsay, Carolina B.^a | Serrano, Felipe G.^a | Ureta, Roxana C.^a | Theoduloz, Cristina^b | Schmeda-Hirschmann, Guillermo^c | Inestrosa, Nibaldo C.^{a; d; e; *}

Affiliations: [a] Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile | [b] Laboratorio de Cultivo Celular, Facultad de Ciencias de la Salud, Universidad de Talca, Talca, Chile | [c] Laboratorio de Química de Productos Naturales, Instituto de Química de Recursos Naturales, Universidad de Talca, Talca, Chile | [d] Center of Healthy Brain Aging, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia | [e] Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile

Correspondence: [*] Correspondence to: Dr. Nibaldo C. Inestrosa, CARE Biomedical Research Center, Pontifical Catholic University of Chile, Postal Code 8331150, PO Box 114-D, Santiago, Chile. Tel.: +56 2 6862722; Fax: +56 2 6862959; E-mail: ninestrosa@bio.puc.cl.

Abstract: Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer’s disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

Keywords: Amyloid-β, diterpenes, ferruginol, jatrophone, junicedric acid, neuroprotection

DOI: 10.3233/JAD-170701

Journal: Journal of Alzheimer's Disease, vol. 63, no. 2, pp. 705-723, 2018