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Brain aging is one of the major risk factors for the development of several neurodegenerative diseases. Therefore, mitochondrial dysfunction plays an important role in processes of both, brain aging and neurodegeneration. Aged mice including NMRI mice are established model organisms to study physiological and molecular mechanisms of brain aging. However, longitudinal data evaluated in one cohort are rare but are important to understand the aging process of the brain throughout life, especially since pathological changes early in life might pave the way to neurodegeneration in advanced age. To assess the longitudinal course of brain aging, we used a cohort of female NMRI mice and measured brain mitochondrial function, cognitive performance, and molecular markers every 6 months until mice reached the age of 24 months. Furthermore, we measured citrate synthase activity and respiration of isolated brain mitochondria. Mice at the age of three months served as young controls. At six months of age, mitochondria-related genes (complex IV, creb-1, β-AMPK, and Tfam) were significantly elevated. Brain ATP levels were significantly reduced at an age of 18 months while mitochondria respiration was already reduced in middle-aged mice which is in accordance with the monitored impairments in cognitive tests. mRNA expression of genes involved in mitochondrial biogenesis (cAMP response element-binding protein 1 (creb-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), nuclear respiratory factor-1 (Nrf-1), mitochondrial transcription factor A (Tfam), growth-associated protein 43 (GAP43), and synaptophysin 1 (SYP1)) and the antioxidative defense system (catalase (Cat) and superoxide dismutase 2 (SOD2)) was measured and showed significantly decreased expression patterns in the brain starting at an age of 18 months. BDNF expression reached, a maximum after 6 months. On the basis of longitudinal data, our results demonstrate a close connection between the age-related decline of cognitive performance, energy metabolism, and mitochondrial biogenesis during the physiological brain aging process.

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.

BackgroundCurrent approved drugs for Alzheimer’s disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.MethodsThree-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1–40 and Aβ1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.ResultsMH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.ConclusionsMH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0342-6) contains supplementary material, which is available to authorized users.

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Scope 2´‐Fucosyllactose (2´FL) is an abundant oligosaccharide in human milk. It is hypothesized that its brain enrichment is associated with improved learning. Accumulation of 2´FL in organs, biological fluids, and feces is assessed in wild‐type and germ‐free mice. Methods and results 13 C‐labelled 2´FL is applied to NMRI wild‐type mice intravenously (0.2 g kg −1 ) or orally (1 g kg −1 ), while controls receive saline. Biological samples are collected (0.5–15 h) and 13 C‐enrichment is measured by elemental analysis isotope ratio mass spectrometry (EA‐IRMS). After oral application, 2´FL is primarily eliminated in the feces. 13 C‐enrichment in organs including the brain follows the same pattern as in plasma with a maximum peak after 5 h. However, 13 C‐enrichment is only detected when the 13 C‐2´FL bolus reaches the colon. In contrast, in germ‐free mice, the 13 C‐bolus remains in the intestinal content and is expelled via the feces. Furthermore, intravenously applied 13 C‐2´FL is eliminated via urine; no 13 C‐enrichment of organs is observed, suggesting that intact 2´FL is not retained. Conclusions 13 C‐enrichment in brain and other organs after oral application of 13 C‐2´FL in wild‐type mice indicates cleaved fucose or other gut microbial 2´FL metabolites may be incorporated, as opposed to intact 2´FL.

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Scope To further examine the role of the human milk oligosaccharide 2’fucosyllactose (2´FL) and fucose (Fuc) in cognition. Using 13C‐labeled 2’FL,thestudy previously showed in mice that 13C‐enrichment of the brain is not caused by 13C1‐2´FL itself, but rather by microbial metabolites. Here, the study applies 13C1‐Fuc in the same mouse model to investigate its uptake into the brain. Methods and Results Mice received 13C1‐Fuc via oral gavage (2 mmol 13C1‐Fuc/kg‐1 body weight) or intravenously (0.4 mmol/kg‐1 body weight). 13C‐enrichment is measured in organs, including various brain regions, biological fluids and excrements. By EA‐IRMS, the study observes an early rise of 13C‐enrichment in plasma, 30 min after oral dosing. However, 13C‐enrichment in the brain does not occur until 3‐5 h post‐dosing, when the 13C‐Fuc bolus has already reached the lower gut. Therefore, the researcher assume that 13C‐Fuc is absorbed in the upper small intestine but cannot cross the blood‐brain barrier which is also observed after intravenous application of 13C1‐Fuc. Conclusions Late 13C‐enrichment in the rodent brain may be derived from 13C1‐Fuc metabolites derived from bacterial fermentation. The precise role that Fuc or 2´FL metabolites might play in gut‐brain communication needs to be investigated in further studies.