Keywords

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1 Brain Aging: An Inevitable Physiological Process

The aging of the brain is characterized by a decline in several physiological abilities, including sensory, motor, and cognitive functions [78, 85, 87]. In mice, brain aging is typically accompanied by substantial cognitive deficits, beginning in late adulthood at around 12 months of age [90, 127]. Impaired function of signaling mechanisms, altered gene expression, and perturbed energy production are signs of aging on the cellular level. On the molecular level, oxidative stress results in the accumulation of damaged proteins, lipids, carbohydrates, and nucleic acids [33, 104]. Physiological changes that occur during normal aging of the brain may be exacerbated in vulnerable populations of neurons, initiating pathological processes that finally lead to neurodegenerative disorders [87].

2 Aging: An Important Risk Factor for Neurodegeneration

To understand the onset and progression of neurodegenerative diseases is one of the major challenges of the twenty-first century. The United Nations estimate that the number of people suffering from age-related neurodegeneration, particularly from AD, will exponentially increase from 25.5 million in 2000 to an estimated 114 million in 2050 [143]. Several meta-analyses have consistently estimated the global prevalence of dementia in people aged over 60 to be approximately 4 % [101]. The global annual incidence of dementia is estimated to be about 8 per 1,000 population [29], with no substantial variations across continents, except Africa [100]. The incidence rate of dementia increases exponentially, doubling approximately every 5–6 years with age and incidence rates of dementia are quite similar across regions [100, 101, 148]. The largest increase in absolute numbers of old persons will occur in developing countries [100]. Thus, the global trend in the phenomenon of population aging has dramatic consequences on public health, health-care financing, and health care delivery systems in the world [100].

3 Alzheimer’s disease: A Devastating Neurodegenerative Disorder

The clinical symptoms of Alzheimer’ disease (AD) include a progressive loss of memory and impairment of cognitive abilities. Severe neurodegenerative alterations occur in AD brains, including loss of synapses and neurons, atrophy, and the selective depletion of neurotransmitter systems (e.g., acetylcholine) in the hippocampus and cerebral cortex—two brain regions involved in learning and memory [6]. Such defects are mainly observed in the later stage of the disease and have also been partially demonstrated using transgenic animal models of AD [71, 118].

AD is considered as a protein aggregation disorder, based on two key neuropathological hallmarks. One hallmark is the hyperphosphorylation of the tau protein, resulting in the formation of neurofibrillary tangles (NFTs), and the second hallmark is the increased formation and accumulation of amyloid-beta peptide (Aβ) oligomers and fibrils derived from amyloid precursor protein (APP) [42]. Although the exact underlying causes initiating the onset of AD are still unclear, an imbalance in oxidative and nitrosative stress, intimately linked to mitochondrial dysfunction, characterizes early stages of AD pathology [90].

4 Mitochondrial Dysfunction: A Common Event in Brain Aging and Alzheimer’s Disease

Increasing evidence suggests that mitochondrial dysfunction plays an important role in brain aging and in the pathogenesis of neurodegenerative diseases, including AD [24, 48, 78, 82, 83, 86, 116, 135, 141]. Mitochondria are complex, network-forming organelles, involved in different metabolic pathways, e.g., citric acid cycle (TCA), energy transformation, amino-acid metabolism, and urea cycle [95]. Mitochondria consist of inner and outer membranes composed of phospholipid bilayers and proteins. The inner mitochondrial membrane harbors the proteins of the electron transfer system (ETS), responsible for oxidative phosphorylation. The mitochondrial oxidative phosphorylation (OXPHOS) system is the final biochemical pathway that produces energy in form of ATP by consuming oxygen. Electrons are transferred through the complexes of the mitochondrial respiratory system chain and simultaneously, an electrochemical proton gradient is built across the inner mitochondrial membrane, generating the proton-motive force that drives the production of ATP [13, 124].

Alterations of mitochondrial efficiency and function are mainly related to alterations in mitochondrial mass, amount of respiratory enzymes, or changes in enzyme activities [11, 34, 65, 98]. A reduction in mitochondrial content or lowered ETS results in a general limitation of cellular energy production. Dysfunction of single complexes of the respiratory system are frequently accompanied by deleterious side effects, such as loss of mitochondrial membrane potential (MMP) and subsequently decreased ATP levels, but also production of reactive oxygen species (ROS) [91].

Apart from ROS enzymatically produced by NADPH oxidases, cytochrome P450-dependent oxygenases, and xanthine dehydrogenases, mitochondria are regarded as the primary site of ROS production within cells. The ETS constantly generates ROS, which are usually kept in balance by various defense mechanisms, i.e., anti-oxidative molecules (e.g., glutathione (GSH) or vitamin E) and antioxidant enzymes (e.g., superoxide dismutase (SOD), catalase, glutathione peroxidase, and glutathione reductase), as long as ROS levels are in the physiological range. Furthermore, slight uncoupling of the ETS, e.g., by uncoupling proteins, may also reduce ROS production. Low levels of ROS are produced constantly which might have physiological functions as signaling molecules [38]. Functional failure of this system can lead to deleterious effects, which may exaggerate the consequences of mitochondrial dysfunction [46]. Insufficient defense mechanisms and excessive ROS production (e.g., as superoxide anions) can lead to cell damage. The major sources of superoxide anions are redox centers of complex I and III of the ETS, and different mitochondrial flavoproteins. Superoxide is a rather weak radical, but it is the precursor of various, potentially more toxic ROS [13, 69, 92]. Its transformation into hydrogen peroxide and hydroxyl radicals, as well as its participation in the formation of peroxynitrate, creates strong oxidants [31].

The proteins of the OXPHOS system and lipids are key targets of the deleterious effects of ROS, potentially leading to membrane depolarization and subsequently, impaired mitochondrial function [46, 90]. Thus, mitochondria play an important role in producing energy, but also as major source of ROS. Therefore, efforts to increase mitochondrial function should be accompanied by equal efforts to limit deleterious ROS generation.

Early defects in the expression of several subunits of respiratory system chain complexes [106], decreased mitochondrial respiration (mainly mediated by a decline in complex I and complex IV function), and reduced MMP and ATP levels have been detected in several AD cell culture and animal models [59, 73, 106, 141]. Direct effects of APP and Aβ on mitochondrial function may induce this early dysfunction. Accumulation of APP in mitochondria, which has been found in both transgenic cell lines and animals, correlates with mitochondrial dysfunction. This may provide one causal link explaining the impaired energy metabolism and subsequent rise in ROS/RNS in models of AD [5, 37, 58]. Aside from APP, Aβ itself has also been suggested to affect mitochondrial function (Fig. 23.1). Data show that the presence of one of the key enzymes in Aβ release, namely, γ-secretase, pinpoints to a direct production of Aβ in these organelles [45].

Fig. 23.1
figure 1

Increasing evidence suggests that mitochondrial dysfunction plays an important role in brain aging and in the pathogenesis of neurodegenerative diseases. Dysfunction of single complexes of the respiratory system are frequently accompanied by deleterious side effects, such as decreased adenosine triphosphate (ATP) levels, but also production of reactive oxygen species (ROS). Direct effects of Aβ peptides on mitochondrial function may induce early mitochondrial dysfunction and explain the impaired energy metabolism in models of AD. Physiological changes that occur during the normal aging of the brain may be exacerbated in vulnerable populations of neurons, initiating pathological processes that finally lead to neurodegenerative disorders. Rice bran, curcumin, anthocyanin-rich fruits, and olive polyphenols represent promising nutraceuticals for modulating mitochondrial function in the brain

Full size image

Recently, Leuner et al. showed that mitochondria-derived ROS are sufficient to trigger amyloidogenic APP-processing in vivo, and that Aβ itself leads to mitochondrial dysfunction and increased ROS levels (Fig. 23.1) [73]. Finally, increasing evidence suggests that mitochondrial dysfunction in AD originates not only from the deleterious impact of APP/Aβ but also from its interplay with hyper-phosphorylated Tau protein on the mitochondrial level [59].

5 Brain Aging, Dementia, and the Impact of Nutrition

The survival of any organism crucially depends on its nutrient intake, which provides all molecules for cell formation, maintenance and repair, in the form of either ready-made building blocks or precursors [55]. In the case of humans, the importance of nutrition becomes obvious in the form of distinct patterns of clinical symptoms caused by the inadequate intake of one of the macronutrients, vitamins, or minerals [137]. The increase in life expectancy observed in the twentieth century in many populations throughout the world attests to the impact nutrition (in conjunction with better hygiene and medical practice) exerts on human health [97]. At the same time, however, human aging beyond 50 years of age is typically accompanied by the occurrence of one, often more, chronic, age-related diseases, such as cancer, cardio-vascular dieseases, and neurodegeneration [14, 32]. Due to its physiological characteristics, the brain is particularly prone to damage induced by noxious changes or fluctuations in cellular homeodynamics [103, 111]. Thus, the quest for primary prevention of neurodegeneration is imperative.

As stationary autotrophs, plants have evolved numerous pathways for the synthesis of secondary plant metabolites. These phytochemicals act, for example, as free radical scavengers or as defense against infectious microorganisms, with the aim of increasing a plant’s chances for reproduction and survival [60].

In the following sections we discuss rice bran, curcumin, anthocyanin-rich fruits, and olive polyphenols as promising nutraceuticals for modulating mitochondrial function in the brain (Fig. 23.1).

5.1 Rice Bran

With an annual worldwide production of over 600 tons in 2006, rice is one of the most important staple foods, especially in Asian countries. The outer layer of the rice grain is called rice bran and is removed during the rice milling process to produce white rice. As a by-product of the rice milling process, rice bran has an annual production rate of 40–70 million tons per year and usually is used as animal food [28, 53]. Since rice bran contains the enzyme lipase which quickly renders the bran rancid and inedible it has to be stabilized before using it as human aliment, for example in the form of oils and extracts as health food products [53].

Key components of the rice bran are tocopherols, tocotrienols (Fig. 23.2), and γ-oryzanol. Known beneficial health effects of rice bran include anti-inflammatory, cholesterol-lowering, antioxidant, and antidiabetic effects [3, 18, 57, 72]. We recently found that a stabilized rice bran extract (RBE) also improves brain mitochondrial function in guinea pigs by increasing mitochondrial content and resistance against oxidative and nitrosative stress [43]. Therefore, RBE might be a suitable substance for the prevention of mitochondrial dysfunction seen in brain aging and neurodegenerative diseases like AD.

Fig. 23.2
figure 2

Chemical structure of α-, β-, and γ-tocopherol (a) and tocotrienol (b)

Full size image

Tocopherols and tocotrienols are ingredients of rice bran and very likely play an important role in mediating the above mentioned health-promoting effects [21, 30]. In micromolar concentrations, tocopherols as well as tocotrienols act as radical scavengers that react with free radicals to produce less reactive radicals, thus for example preventing lipid peroxidation in membranes and lipoproteins [96, 144]. At a concentration of 5 μM, a tocotrienol-rich fraction from palm oil was, for example, able to inhibit oxidative damage in lipids and proteins from rat brain mitochondria induced by ascorbate-Fe2+, the free radical initiator azobis(2-amidopropane)dihydrochloride (AAPH) and photosensitization [54]. Supplementary vitamin E also prevented mitochondrial dysfunction in rat liver perfused with tert-butylhydroperoxide to induce lipid peroxidation by decreasing oxidative stress [44]. Altogether, tocotrienols seem to be better antioxidants than tocopherols, probably due to their faster recycling and better membrane distribution [113, 117]. Micromolar concentrations of tocopherols and tocotrienols that show antioxidative effects can usually not be reached in plasma and brain tissue by means of oral administration. On the other hand it has been reported that nanomolar concentrations of tocotrienols are sufficient to exert neuroprotective effects since they are able to modify several enzymes and signaling pathways in brain cells. Nanomolar concentrations of tocotrienols can be reached in human plasma after tocotrienol supplementation [30]. Among the cellular targets of tocotrienols are prenyl transferases [146], phospholipase A2 [61], 12-lipoxygenase [62], and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) [35, 129].

Vitamin E has also been reported to directly interact with mitochondria [81], another possible mechanism for the neuroprotective potential of vitamin E. Dietary supplementation of rats with vitamin E (2.0 or 5.0 g/kg of food) for 3 months, for example, restored the age-dependent decrease in mitochondrial respiration and prevented an increase in oxidation products [93]. These effects are comparable to the increase in mitochondrial function seen in guinea pigs fed with RBE for 3 weeks [43], indicating that vitamin E at least partly accounts for the mitochondria-protective effects of RBE.

Another key ingredient of rice bran is γ-oryzanol, a mix of ferulic acid esters of triterpene alcohol and phytosterols (Fig. 23.3) [72]. Antitumoral as well as antioxidant properties (e.g., inhibition of lipid peroxidation) and the lowering of blood cholesterol levels are the main known biological effects of γ-oryzanol [3, 64, 99]. Since γ-oryzanol is not water-soluble, it has a very low bioavailability when orally administered [63]. It is largely de-ferulated in the gut [12], but no enhanced ferulic acid concentrations could be detected in plasma after oral administration of RBE to guinea pigs [43], confirming the low bioavailability.

Fig. 23.3
figure 3

Chemical structure of cycloartenyl ferulate, an exemplary member of the γ-oryzanol family which is a mix of ferulic acid esters of triterpene alcohol and phytosterols

Full size image

We found that RBE enhances mitochondrial function by increasing mitochondrial content via activation of the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) [43]. One activator of PGC-1α is AMP-activated kinase (AMPK) which is, amongst others, induced by certain polyphenols, including resveratrol [77]. Therefore, it seems likely that RBE contains polyphenols or similar compounds able to activate PGC-1α. Identification of these compounds will have to be the subject of further upcoming studies.

Due to the observed beneficial effects of its main ingredients on neurons and the beneficial effects of RBE on mitochondrial function, rice bran appears to be a very promising substance for the long-term prevention of neurodegeneration and the development of neurodegenerative diseases. Further studies need to be accomplished to examine the effects of rice bran administration in aging and neurodegenerative conditions.

5.2 Curcumin

Curcumin, demethoxycurcumin, and bisdemethoxycurcumin are derived from the rhizome of the plant curcuma longa (Fig. 23.4). This plant has long been known as a spice, a dye, and a remedy especially in Asian countries before it became generally and worldwide common as main ingredient of curry powder. Apart from the use as spice, curcumin is also applied as food additive (E100) and a pigment in textile and cosmetic industry [27]. Curcumin has been associated with various beneficial health effects, among them antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, wound-healing, and anticancer properties [1, 40, 149]. Additionally curcumin has been shown to inhibit Aβ aggregation and reduce amyloid plaque burden in transgenic mouse models of AD [10, 75]. Taking all these effects into account, curcumin is assumed to have potential to act against various chronic diseases like diabetes, allergies, arthritis, and AD [1].

Fig. 23.4
figure 4

Chemical structure of curcumin (keto form)

Full size image

Epidemiologic evidence suggests that regular curry consumption decreases AD risk in elderly people. The Indo-US Study compared AD incidence rates in a rural, population-based cohort in India to those of a reference US population in Pennsylvania and found that AD incidence rates in India, where people consume curry spice on a daily basis, are much lower than those in the USA [16]. Ng and coworkers reported that regular curry consumption is correlated with better cognitive function in non-demented elderly Asians [94].

The antioxidative and anti-inflammatory effects of curcumin as well as its ability to inhibit protein aggregation seem to be the most important properties for the potential of curcumin against neurodegenerative diseases [22]. A lot of preclinical in vitro and in vivo studies have been accomplished to verify the beneficial effects of curcumin in neurotoxicity and AD. Apart from the reduction of amyloid plaque formation, curcumin also decreased oxidative injury, DNA damage, cytokine formation and memory deficits in mouse and rat models of AD [20, 22]. In a homocysteine-induced rat neurotoxicity model, i.p. curcumin treatment (5 and 50 mg/kg body weight) for 10 days led to a significant decrease in malondialdehyde and superoxide anion levels, rescued hippocampal cells, and improved learning and memory [8]. In an Alzheimer transgenic APPsw mouse model (Tg2576), 6 month curcumin administration via a pelleted diet (160 and 5,000 ppm) decreased oxidized protein and interleukin-1β content in the brain. Insoluble and soluble Aβ concentrations as well as plaque burden were decreased in mouse brains by low-dose curcumin administration [75].

Curcumin has been shown to have beneficial effects on mitochondrial function, for example by inhibiting lipid peroxidation and protein oxidation in rat liver mitochondria [142]. It further counteracted tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in rat cortical neurons by rescuing mitochondrial membrane potential, decreasing cytochrome c release and preventing apoptosis [147]. In the brains of streptozotocin-induced diabetic rats, activities of respiratory complexes I and IV were downregulated, and ATP levels were reduced. Curcumin administration to these rats (120 mg/kg bw p.o. for 4 weeks) rescued respiratory enzyme complex activities and restored ATP levels [102]. We recently showed that 5 month feeding of curcumin (500 mg curcumin per kg diet) was able to compensate mitochondrial dysfunction in a mouse model of accelerated aging. Thereby curcumin elevated the mitochondrial membrane potential, ATP levels, restored mitochondrial fusion processes, and elevated protein levels of PGC1α [25]. Since mitochondrial dysfunction plays a major role in aging as well as in the development of neurodegenerative diseases, this mechanism of action of curcumin might very well contribute to the observed beneficial effects of curcumin on neurodegeneration. Various in vitro and in vivo studies have also reported beneficial effects of curcuminoids in chemically induced cell culture and rodent models of Parkinson’s Disease (summarized by [22]).

Molecular mechanisms of action of curcumin mainly comprise its activity as radical scavenger, its antioxidant and anti-inflammatory effects mediated through nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and NF-κB as well as epigenetic modulations. Due to its chemical structure, curcumin is a potent scavenger of free radicals [2, 133]. Additionally, curcumin also exerts antioxidant effects by activating Nrf2, a transcription factor that controls the expression of antioxidant and phase-II enzymes, for example heme oxygenase and glutathione synthesis enzymes [109, 145]. By diminishing ROS production via radical scavenging and upregulation of antioxidative enzymes, curcumin contributes to keeping oxidative stress in the cell low, thus amongst others protecting mitochondrial function [102, 125]. Curcumin inhibits NF-κB, a transcription factor controlling the expression of pro-inflammatory molecules (e.g., cytokines) [52, 56, 128]. In conditions of neurodegeneration or AD, microglia in the brain become activated and produce pro-inflammatory responses via NF-κB [84]. Curcumin is able to inhibit these inflammatory responses in microglia cells, thus contributing to the prevention of neurodegeneration and AD development [49, 139].

Despite these very promising in vitro and in vivo results, no clinical studies testing curucmin in MCI or AD patients have reported positive outcome so far. Two 24-week intervention studies with patients with possible/probable or mild to moderate AD receiving curcumin doses up to 4 g/day reported no changes in clinical or biomarker measures between the study groups [9, 107]. Probable reasons might be the choice of subjects or the low bioavailability of curcumin. The best time for prevention in sporadic AD is the preclinical stage when neurodegeneration has already started but no clinical symptoms have yet occurred [136]. Therefore, neurodegeneration might have been too far advanced in the subjects included in these studies to be able to detect positive curcumin effects. Phase I clinical trials have proven that curcumin is well tolerated even in high doses (up to 12 g), but oral bioavailability is very low (plasma levels often below 1 μM) [27]. Curcumin concentrations in the brains of mice were in the low ng/g tissue range 45 min after oral administration of 120 mg curcumin/kg body weight (unpublished data). Probable reasons for the low bioavailability are poor absorption, rapid metabolism, and rapid systemic elimination of curcumin [4, 17].

To increase curcumin bioavailability, several different approaches have been pursued. One is the simultaneous administration of other secondary plant compounds like piperine which inhibit hepatic and intestinal metabolism of curcumin and are able to increase curcumin bioavailability significantly [120]. Other approaches comprise the production of curcumin nanoparticles or liposome-encapsulated curcumin [70, 130]. We recently showed that administration of curcumin micelles (AquaNova, Darmstadt, Germany) for 45 min increased curcumin plasma concentrations 50-fold in C57BL/6 mice, curcumin brain concentrations were increased sixfold (unpublished data).

Altogether, curcumin appears to be a promising food ingredient to help in the prevention of neurodegeneration seen in aging and, for example, in Alzheimer’s Disease. To display its protective effects, data from clinical and epidemiological studies suggest that curcumin might have to be administered over an extended period of time starting before the onset of clinical symptoms of neurodegeneration. This long-term preventive effect of curcumin will have to be proven in upcoming clinical trials.

5.3 Anthocyanin-Rich Fruits

In the last decade, colorful fruits have emerged as potential neuroprotective food components. Many animal intervention studies with blueberry, blackberry, strawberry, mulberry, Concord grape, and pomegranate provide evidence of the beneficial effects of colorful fruits on aging (especially on age-related cognitive and motor decline) and neurodegeneration. Anthocyanins, a flavonoid subgroup (Fig. 23.5) with high antioxidant potential, are responsible for the characteristic bright colors in these fruits and may also account at least in part for their neuroprotective activity [110, 140].

Fig. 23.5
figure 5

Basic structure of anthocyanin aglycone and substituents of the 6 main structures found in food. In plant material anthocyanins are usually present as 3-glycoside and 3′ 5-glycoside [19]

Full size image

In the late nineties, James Joseph and colleagues showed that feeding diets with high antioxidant potential might prevent and even reverse age-related deficits in motor and cognitive behavior in Fischer 344 (F344) rats. However, although based on equal antioxidant activity, the supplementations with blueberry and strawberry did not lead to the same improvement in behavioral performance. Blueberry supplementation ameliorated both motor and cognitive performance, whereas strawberry supplementation only led to an improvement in motor performance suggesting that simple antioxidant activity is not the sole explanation for the neuroprotective activity [51]. To date, the theory that flavonoids like anthocyanins exert their effects by direct scavenging of reactive-oxygen-species (ROS) is more and more replaced by the assumption that they act by indirect antioxidant activity and activation of signaling pathways [7, 112]. Supporting evidence for this theory comes from bioavailability studies that often report <0.1 % recovery of ingested anthocyanins in the urine [88, 110]. Like all polyphenols, anthocyanins are subject to various degradation and biotransformation processes leading to a variety of metabolites in the human body. Moreover, to exert direct effects in the brain anthocyanins also have to cross the blood–brain barrier (BBB) separating the CNS from the body periphery. Feeding studies with rodents and pigs have been shown that anthocyanins are able to cross the BBB. After 15 days of supplementation with blackberry extract [131] and 2 h of administration of the anthocyanidin pelargonidin (50 mg/body weight) [26], 0.25 nmol anthocyanins/g and 0.16 nmol pelargonidin/g tissue, respectively, were detected in rat brain. Moreover, data from pigs suggest that anthocyanins may accumulate in brain tissue. After a feeding period with 1–4 % blueberries for 4 weeks, fasted pigs showed anthocyanin concentration of about 0.3–0.4 ng/g tissue in the brain but not in plasma or urine. However, there is a lack of data concerning the presence of anthocyanin metabolites which are suggested to account at least in part for the in vivo effects of anthocyanin-rich fruits [110].

Regarding neuroprotection, the most extensively studied anthocyanin-rich diet in rodents is the 2 % blueberry-supplemented diet which led to improvements in cognitive and motor performance of aged rats or models of increased oxidative stress or inflammation [15, 23, 36, 105, 122]. The recent work by Rendeiro and colleagues strengthens the theory that the containing flavonoids represent causal neuroprotective agents in the blueberry diet. Purified blueberry anthocyanins in equivalent doses to the whole blueberry extract led to the same improvement of spatial working memory performance as whole blueberry-diet [105]. Several other anthocyanin-rich fruits have shown to have a beneficial impact on behavioral performance of rodents. However, there seem to be differences in the activity that might be fruit or flavonoid specific as well as concentration-dependent. For example, Concord grape juice in a concentration of 10 % in drinking water improved cognitive performance in aged F344 rats whereas a concentration of 50 % of the juice ameliorated motor function [121]. 2 % blueberry and 2 % strawberry extract diets protected differently from 56Fe particle irradiation which induces oxidative stress, inflammation and behavioral deficits similar to those seen in aging. Strawberry-supplemented rats had a better ability to retain place information (reduced spatial deficits) linked to hippocampus-mediated behavior, blueberry-supplemented rats, in contrast, showed improved reversal learning which is more dependent on intact striatal function [122]. Nevertheless, a recent study showed that 56Fe particle irradiation causes downregulation of genes involved in protective stress signaling which could be ameliorated by blueberry- or strawberry-supplemented diets to a similar extent [123].

A great deal of research has concentrated on the impact of berry fruits and flavonoids on signaling cascades (reviewed in [89, 126]). In this regard, studies on the mechanism of cognitive effects of blueberry diet in rats revealed an involvement of neurogenesis, neurotrophic factor insulin-like growth factor-1 (IGF-1) and its receptor, as well as mitogen-activated protein (MAP) kinase signal transduction [15]. Grape powder in drinking water of rats (15 g/L) prevented the l-buthionine-(S,R)-sulfoximine induced oxidative stress and cognitive impairment as well as prevented the activation of brain extracellular signal-regulated kinase-1/2 (ERK-1/2) and decrease of glyoxalase-1 (GLO-1), glutathione reductase-1 (GSR-1), calcium/calmodulin-dependent protein kinase type IV (CAMK-IV), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) levels [150]. Research also concentrated on the effects of purple sweet potato color (PSPC) which is composed of a mixture of anthocyanins. PSPC (100 mg/kg) attenuated d-galactose-induced aging related changes in mouse brain after oral administration for 4 weeks. The improvement of behavioral performance was accompanied by an enhanced activity of the antioxidant enzymes copper/zinc superoxide dismutase and catalase, less oxidative brain damage measured as malondialdehyde, and diminished parameters related to neuroinflammation (e.g., nuclear translocation of NF-κB) [118]. Further studies using this model also revealed the ability of PSPC to counteract the onset of neuronal apoptosis by promoting survival mechanisms which involves ERK 1/2, phosphoinositide 3-kinase (PI3K), Akt, and c-Jun NH2-terminal kinase (JNK) [80]. Recently, PSPC (200 mg/kg for 4 weeks) has also been tested in a mouse model of cognitive impairment induced by hippocampal mitochondrial dysfunction in mice that were treated with the neurotoxin domoic acid. The study results suggest that better cognitive performance involved estrogen receptor-α-mediated mitochondrial biogenesis signaling, restored mitochondrial dysfunction, decreased ROS and protein carbonyl levels, and suppressed endoplasmic reticulum stress-induced apoptosis [79]. Further evidence for the amelioration of mitochondrial dysfunction is provided by a study with anthocyanins from grape skin in rats with transient memory impairment and mitochondrial dysfunction induced by scopolamine. The i.p. treatment with 200 mg/kg grape skin anthocyanins reversed the impairment of memory and restored ATP levels in hippocampus and cerebral cortex [41]. Mitochondrial dysfunction has also been investigated in cell cultures treated with protocatechuic acid, a well-known metabolite of the anthocyanidin cyanidin, which has been detected in the bloodstream of humans [138] and rats [134] after consumption of cyanidin glucoside/cyanidin-glucoside-rich foods. Protocatechuic acid was effective to decrease mitochondrial dysfunction and apoptotic cell death induced by rotenone [39] and 1-methyl-4-phenylpyridinium ion [76] in the neuronal-like cell line PC 12. Moreover, treatment of human neuroblastoma SK-N-MC cells with metabolites obtained from in vitro digestion of wild blackberry extract was effective in diminishing ROS, modulating GSH and maintaining high mMP at levels approaching concentrations that are described for human plasma [132].

Mitochondrial dysfunction, oxidative stress, and inflammation occur not only in aging but also in age-related neurodegenerative changes (Fig. 23.1). Slowing down or even preventing aging processes in the brain by nutritional approaches might therefore as well contribute to the prevention of neurodegenerative diseases like Alzheimer’s disease. Anthocyanin-rich fruits have a beneficial in mouse models of AD. In amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice diet supplementation with 2 % blueberry extract from 4 months of age prevented behavioral deficits assessed at 12 months of age as well as enhanced memory-associated neuronal signaling. No changes in Aβ burden were observed [50]. However, less accumulation of soluble Aβ42 and amyloid deposition was observed in the hippocampus of APP transgenic mice after the treatment with pomegranate juice concentrate in drinking water (1:80 or 1:160 dilution) for 6.5 months [47]. In APP/PS1 transgenic mice drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 months led to improved spatial learning and memory, decreased Aβ plaque load, reduced microgliosis as well as lowered tumor necrosis factor a (TNF-α) concentrations and nuclear factor of activated T-cell (NFAT) transcriptional activity [108]. Additionally, 0.18 or 0.9 % mulberry extract supplemented diet for 3 months led to a decreased accumulation of Aβ as well as higher antioxidant enzyme activity and less lipid oxidation in the brain of senescence-accelerated mouse prone 8 (SAMP8) mice [119].

Importantly, preliminary studies in older adults with mild cognitive impairment (MCI) show beneficial effects of Concord grape and blueberry juice [66–68]. MCI is the first clinical appearance of neurodegeneration accompanied by increased risk for dementia. In many individuals MCI progresses to AD. The consumption of wild blueberry juice (6 and 9 mL/kg) for 12 weeks improved paired associate learning in the Verbal Paired Associate Learning Test (V-PAL) and word list recall in the California Verbal Learning Test (CVLT) in 9 older adults with MCI [68]. In a similar study 12 older adults with MCI showed improved verbal learning in CVLT and a trend toward improved performance with respect to delayed verbal recall and spatial memory after the consumption of Concord grape juice (6 and 9 mL/kg) for a period of 12 weeks [67]. Recently, Concord juice treatment of MCI individuals for 16 weeks reduced semantic interference on memory tasks and led to a relatively greater activation in anterior and posterior regions of the right hemisphere detected using functional magnetic resonance imaging [66].

5.4 Olive Oil Polyphenols

Olive oil is a typical component of Mediterranean diets which have been related to many health beneficial effects including the improvement of cognitive decline. Interestingly, the health benefits of extra virgin olive oil (EVOO) seem to be not only due to its high amount of mono-unsaturated fatty acids but also due to phenolic minor components such as hydroxytyrosol [110]. The phenols present in the native olive fruit differ from those in EVOO. Olives mainly contain the glycosides oleuropein and ligstroside that are degraded to their aglycones and various derivates during ripening. The aglycones and derivates are the most abundant phenols in olive oil. Hydroxytyrosol and tyrosol are the end products of the hydrolysis of those aglycones in olive oil (Fig. 23.6) [154].

Fig. 23.6
figure 6

Olive oil phenols (a) Oleuropein aglycone (b) Hydroxytyrosol

Full size image

Recently, EVOO showed beneficial effects in SAMP8 mice, a model of age-related learning/memory impairment associated with increased amyloid-β protein and brain oxidative damage [151]. The oral administration of EVOO (75 μL/kg body weight) for 6 weeks improved cognitive function and oxidative brain damage in aged SAMP8 mice. Interestingly, mice that received EVOO with enhanced amount of olive oil polyphenols showed a greater improvement in both cognitive function and oxidative damage than mice that received regular EVOO [151]. Additionally, mice treated with EVOO (10 % wt/wt dry diet) rich in phenols (6 mg/kg polyphenols/day) from middle age to senescence had improved contextual memory in the step-down test and a better performance in motor coordination in the rotarod test [152].

Data from human and animal studies indicate that olive oil phenols are well absorbed and underlie biotransformation processes common for polyphenols in general [154]. As ortho-diphenol, hydroxytyrosol contributes significantly to the oxidation stability of olive oil and is attracting particular attention as antioxidant [154, 110]. However, the intake of phenols in the amounts provided by dietary olive oil is suggested to be too low for direct antioxidant activity in the human body [154]. Several studies therefore concentrated on hydroxytyrosol-rich extracts. Importantly, conjugated hydroxytyrosol was detected in brain tissue of rats (50 nmol/g) after a single dose of a phenolic extract of olive cake (3 g/kg body weight) [153]. An interesting source of hydroxytyrosol is olive mill water waste which is currently discarded. Olive mill water waste is very rich in polyphenols that can be recovered by ad hoc techniques [110]. Hydroxytyrosol-rich extract, prepared from olive mill water waste administrated to mice (100 mg/kg) for 12 days led to a moderate, although statistically significant hyperpolarization of mitochondria in dissociated mouse brain cells [115] which is an effect that has been related to a decreased rate of cell death [74]. Moreover, hydroxytyrosol-rich extract was effective to reduce iron-stimulated lipid peroxidation ex vivo, suggesting a neuroprotective effect of hydroxytyrosol intake [115]. Recent in vitro data mainly confirm our previous observation of promising cytoprotection of brain cells by HT-rich olive mill waste water extract in different stressor paradigms [114]. Furthermore, correlation analyses revealed that the observed cytoprotective effects in PC12 cells are likely due to HT present in the extract.

In summary, aging of the brain is characterized by a decline in several physiological abilities, including sensory, motor, and cognitive functions. Physiological changes that occur during normal aging of the brain may be exacerbated in vulnerable populations of neurons, initiating pathological processes that finally lead to neurodegenerative disorders, especially to AD. The incidence rate of AD increases exponentially, doubling approximately every 5–6 years with age. The global trend in the phenomenon of population aging has dramatic consequences on public health, health-care financing, and health care delivery system in the world, especially in developing countries. Increasing evidence suggests that mitochondrial dysfunction plays an important role in brain aging and in the pathogenesis of neurodegenerative diseases. The survival of any organism crucially depends on its nutrient intake, which provides all molecules for cell formation, maintenance and repair, either in the form of ready-made building blocks or precursors. Rice bran, curcumin, anthocyanin-rich fruits, and olive polyphenols are promising nutraceuticals for modulating mitochondrial function in the brain and might contribute to the prevention of AD.