Effects of Long-Term Treatment with a Blend of Highly Purified Olive Secoiridoids on Cognition and Brain ATP Levels in Aged NMRI Mice

Abstract

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer's disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

Cerebral Mitochondrial Function and Cognitive Performance during Aging: A Longitudinal Study in NMRI Mice

“…Based on these data, one would expect a reduced respiration of the respiratory chain complexes [74,75]. Accordingly, in the current study, activity of respiratory chain complexes I and IV as well as CI+CII and CII ETS was significantly reduced starting at 12 months of age compared to that of young animals (Tables 3 and 4) which is in accordance with previous studies of our group detecting reduced complex activity in brains of 18-month-old animals [28,29]. Surprisingly, our longitudinal study shows that complex activity seems to be reduced already in middle-aged animals while brain ATP and MMP levels stay constant until mice reach the age of 18 and 24 months.…”

“…In accordance with most of the previous studies from our group, we measured significantly reduced ATP levels in dissociated brain cells isolated from brains of 18month-old NMRI mice in comparison to young control animals. In accordance with the finding of reduced ATP levels in brains of aged NMRI mice, we found reduced mRNA expression levels of complex IV in the brain of 18-month-old mice, which is one of the most important protein complexes involved in the oxidative phosphorylation process consistent with previous studies [28,29,39]. A reduced complex IV expression was associated with an increase in apoptosis [69,70].…”

“…Furthermore, overexpression of Tfam is able to reverse age-dependent memory loss in mice which shows the close connection between the detected cognitive impairments and the reduced mRNA expression of genes involved in mitochondrial biogenesis found in aged mice [78]. In contrast to our previous work which described a reduced gene expression in brains of 18month-old mice [28,29], in this longitudinal study, we were only able to confirm a reduced mRNA expression of most of the considered genes in brains of mice aged 24 months. We therefore hypothesize that rodents can keep physiological mRNA expression until at least the age of 18 months, but the decrease detected at 24 months of age is finally a result of the ongoing senescence [75].…”

“…Membrane Potential (MMP). ATP and MMP levels were measured in dissociated brain cells (DBCs) of 3-, 6-, 12-, 18-, and 24-month-old NMRI mice [28,39]. ATP levels of 6-and 12-month-old mice showed no significant changes compared to those of young control animals.…”

“…Therefore, we measured the development of the energy metabolism and mRNA expression of genes involved in mitochondrial biogenesis, antioxidant capacity, and synaptic plasticity in the brain as well as the cognitive performance every six months in the same cohort of female NMRI mice. Female NMRI mice are a well-described outbred mouse model for the physiological, "normal" aging process which reflects a high variability of the genome [27][28][29]. This model has been described as most suitable for studies on physiological aging compared to inbred or genetically modified mouse models with accelerated aging or reduced lifespans [30,31].…”