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Exp Neurol. 2020 Feb 19;328:113248. doi: 10.1016/j.expneurol.2020.113248. [Epub ahead of print]

Purified oleocanthal and ligstroside protect against mitochondrial dysfunction in models of early Alzheimer's disease and brain ageing.

Author information

1
Institute of Nutritional Sciences, Laboratory for Nutrition in Prevention and Therapy, Justus-Liebig-University of Giessen, Biomedical Research Center Seltersberg (BFS), Schubertstr. 81, 35392 Giessen, Germany.
2
N-ZymeBioTec GmbH, Haasstraße 9, 64293 Darmstadt, Germany.
3
Institute of Nutritional Sciences, Laboratory for Nutrition in Prevention and Therapy, Justus-Liebig-University of Giessen, Biomedical Research Center Seltersberg (BFS), Schubertstr. 81, 35392 Giessen, Germany. Electronic address: gunter.eckert@ernaehrung.uni-giessen.de.

Abstract

As components of the Mediterranean diet (MedDiet) olive polyphenols may play a crucial role for the prevention of Alzheimer's disease (AD). Since mitochondrial dysfunction is involved in both, brain ageing and early AD, effects of 10 different purified phenolic secoiridoids (hydroxytyrosol, tyrosol, oleacein, oleuroside, oleuroside aglycon, oleuropein, oleocanthal, ligstroside, ligstroside aglycone and ligustaloside B) and two metabolites (the plant metabolite elenolic acid and the mammalian metabolite homovanillic acid) were tested in very low doses on mitochondrial function in SH-SY5Y-APP695 cells - a cellular model of early AD. All tested secoiridoids significantly increased basal adenosine triphosphate (ATP) levels in SY5Y-APP695 cells. Oleacein, oleuroside, oleocanthal and ligstroside showed the highest effect on ATP levels and were additionally tested on mitochondrial respiration. Only oleocanthal and ligstroside were able to enhance the capacity of respiratory chain complexes. To investigate their underlying molecular mechanisms, the expression of genes associated with mitochondrial biogenesis, respiration and antioxidative capacity (PGC-1α, SIRT1, CREB1, NRF1, TFAM, complex I, IV and V, GPx1, SOD2, CAT) were determined using qRT-PCR. Exclusively ligstroside increased mRNA expression of SIRT1, CREB1, complex I, and GPx1. Furthermore, oleocanthal but not ligstroside decreased Aβ 1-40 levels in SH-SY5Y-APP695 cells. To investigate the in vivo effects of purified secoiridoids, the two most promising compounds (oleocanthal and ligstroside) were tested in a mouse model of ageing. Female NMRI mice, aged 12 months, received a diet supplemented with 50 mg/kg oleocanthal or ligstroside for 6 months (equivalent to 6.25 mg/kg b.w.). Young (3 months) and aged (18 months) mice served as controls. Ligstroside fed mice showed improved spatial working memory. Furthermore, ligstroside restored brain ATP levels in aged mice and led to a significant life extension compared to aged control animals. Our findings indicate that purified ligstroside has outstanding performance on mitochondrial bioenergetics in models of early AD and brain ageing by mechanisms that may not interfere with Aβ production. Additionally, ligstroside expanded the lifespan in aged mice and enhanced cognitive function.

KEYWORDS:

Ageing; Mitochondrial dysfunction; Neurodegeneration; Olive secoiridoids

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no conflict of interest.

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