Effects of highly purified olive polyphenols on mitochondrial function in a cellular model of Alzheimer´s disease

Abstract

In the past decades life expectancy has increased substantially which is accompanied with an increase in diseases such as the neurodegenerative disorder Alzheimer disease (AD). AD is a multifactorial disease with a complex pathobiology marked by declines in memory and thinking which is associated with a high social and economic burden. Today, over 47 million people suffer from the most common form of dementia. The prevalence of AD is expected to triple by 2050. Although the disease has been described over a century ago, there is no cure yet. Over 25 years, amyloid-beta is the primary target in most clinical trials. The lack of success in AD drug development is amongst others explained by intervening at a state where the disease progression is too advanced. Additionally, many cell and animal models mimic the familial form of AD. This form of AD represents only a small number of patients, whereas the late-onset AD, with over 90% is more common. Therefore, we established a cell model for the late-onset AD, using SH-SY5Y-APP695 neuronal cells stably expressing the human APP695 isoform. We observed Aβ1-40 expression in a picomolar range, which is representative for the sporadic form of AD. Since mitochondrial dysfunction is involved in both, brain ageing and early states of AD, we investigated mitochondrial parameters in APP695 transfected cells. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) levels as well as the capacity of mitochondrial respiration were significantly decreased. Furthermore, genes of mitochondrial biogenesis and genes of the antioxidative defence system were significant lower expressed. Quantitative analyses of mitochondrial proteins were additionally impaired. As components of the Mediterranean diet (MedDiet), olive polyphenols may play a crucial role for the prevention of AD. Therefore, we investigated in the second part of the present work, effects of 10 different highly purified phenolic secoiridoids (hydroxytyrosol, tyrosol, oleacein, oleuroside, oleuroside aglycone, oleuropein, oleocanthal, ligstroside, ligstroside aglycone and ligustaloside B) and two metabolites (the plant metabolite elenolic acid and the mammalian metabolite homovanillic acid) in very low doses on mitochondrial function in SH-SY5Y-APP695 cells. All tested secoiridoids significantly increased basal ATP levels in the present cell model. 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 significantly 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 in SH-SY5Y-APP695 cells. Furthermore, oleocanthal but not ligstroside decreased Aβ1–40 levels in SH-SY5Y-APP695 cells. Our findings indicate that purified ligstroside has outstanding performance on mitochondrial bioenergetics in a cell model of late-onset AD by mechanisms that may not interfere with Aβ production.