The influence of common free radicals and antioxidants on development of Alzheimer’s Disease

Biomedicine & Pharmacotherapy Volume 78, March 2016, Pages 39-49 Biomedicine & Pharmacotherapy Review Author links open overlay panelKarolina A.Wojtunik-KuleszaaAnnaOniszczukaTomaszOniszczukbMonikaWaksmundzka-Hajnosa a Department of Inorganic Chemistry, Medical University of Lublin, Chodzki 4a, 20-093 Lublin, Poland b Department of Food Process Engineering, Lublin University of Life Sciences, 44 Doświadczalna Street, 20-236 Lublin, Poland https://doi.org/10.1016/j.biopha.2015.12.024 Get rights and content Abstract Alzheimer’s Disease (AD) is one of the most important neurodegenerative disorders in the 21st century for the continually aging population. Despite an increasing number of patients, there are only few drugs to treat the disease. Numerous studies have shown several causes of the disorder, one of the most important being oxidative stress. Oxidative stress is connected with a disturbance between the levels of free radicals and antioxidants in organisms. Solutions to this problem are antioxidants, which counteract the negative impact of the reactive molecules. Unfortunately, the currently available drugs against AD do not exhibit activity toward these structures. Due to the fact that natural substances are extremely significant in new drug development, numerous studies are focused on substances which exhibit a few activities including antioxidants and other anti-AD behaviors. This review article presents the most important studies connected with the influence of free radicals on development of AD and antioxidants as potential drugs toward AD. Keywords Alzheimer’s Disease Oxidative stress Scavenging of free radicals Natural substances 1. Introduction Oxygen, the most significant and essential element, on the one hand is obligatory for aerobic organisms but on the other can cause oxidative damages in cells. Oxidative damages concern each type of cell and biological molecule, including those most important for life, DNA, RNA, protein enzymes, unsaturated lipids, etc [1]. The aforementioned damages lead to numerous disorders such as neurodegenerative, cardiovascular, cancer, etc. Changes made by the negative influence of oxygen is directly connected with molecules formed by oxygen; namely free radicals. These structures, which will be accurately characterized in next part of the paper, include numerous molecules that contain points of similarity such as one or more unpaired electrons. This group can include additional, non-radical oxidative substances such as hydrogen peroxide H2O2 or dinitrogen trioxide N2O3, which form groups of reactive oxygen species, ROS and reactive nitrogen species, RNS [2,3]. These molecules can form as either endogenous or exogenous depending on differing factors. A properly functioning organism can counteract the formation of high amount of these molecules. But in numerous cases, there are disorders leading to an imbalance between free radicals and the scavenging of the molecules, which results in oxidative stress. This phenomenon is presented as one of the causes of many diseases and premature aging. According to main aim of the paper, oxidative stress is introduced as one of the essential causes of the most common neurodegenerative disordeR—Alzheimer’s Disease [4]. Long-standing studies have revealed numerous factors leading to mild cognitive impairment and dementia. Particular attention was paid to Alzheimer’s due to the fact that this problem is affecting an increasing number of people at a younger and younger age. Scientists have uncovered a few causes of the disease, putting particular emphasis on a decreasing amount of neurotransmitter acetylcholine ACh, oxidative stress and senile plaques [5]. This phenomenon motivates scientific researchers to increase studies toward an explanation of these factors and ways to limitation or elimination. Specifically, attention is paid to natural substances which can be the basis for new medicines. Currently available drugs on Alzheimer’s Disease are natural substances such as galantamine, obtained from the bulbs and flowers of Galanthus caucasicus[6]. Unfortunately, this substance is only active toward the inhibition of acetylcholinesterase AChE without impact on the other causes of the disease. Substances acting on a few of the disease’s factors are the most desirable among new compounds. The main goal of the presented paper is to show the influence of free radicals on the emergence and development of AD and potential paths to the reduction of this phenomenon. 2. Reactive oxygen species and reactive nitrogen species According to what was mentioned in the introduction, free radicals are molecules with one or two unpaired electrons. This group can be extended by the addition of other compounds which are not radicals but reveal oxidant properties. This group includes compounds such as hydrogen peroxide H2O2, ozone O3, nitrous acid HNO2, dinitrogen trioxide N2O3, etc. [7]. Despite the lack of an unpaired electron, these molecules can easily react with other molecules, leading to the formation of free radicals or damage to the cell’s organelles. Radicals and non-radical active compounds can be assigned into two groups; reactive oxygen species ROS and reactive nitrogen species RNS. Each of the groups include both free radicals with unpaired electron and non-radical reactive derivatives [8–10]. The difference between them is a nitrogen atom, present in RNS. Fig. 1 presents the most important free radicals and their active derivatives. Examples of reactive forms divided into reactive oxygen and nitrogen species Download full-size image Fig. 1. Examples of reactive forms divided into reactive oxygen and nitrogen species. Radical oxygen species develop as both endogenous and exogenous. In each case, these biochemical reactions lead to the formation of new reactive molecules, capable of attacking membranes or other parts of the cell. They can oxidize aldehydes, amino acids, unsaturated fatty acids and other important compounds in human organism [3]. Each of the molecules is characterized by a different reactivity and selectivity. It is worth pointing out that reactivity and selectivity have an inverse relationship. Confirmation of this phenomenon can be seen in the higher reactivity of hydroxyl radical OH, the most active, which indicates weaker selectivity than superoxide radical anion O2− which exhibits weaker activity. Specific attention should be paid to the reactivity of the hydroxyl radical. These molecules are the most harmful among reactive structures. It has been proven that reactivity of hydroxyl radical is limited by coming across other molecules which can be attacked by the reactive structure. It is able to damage almost all organelle and cell structure, leading to mutation and development of numerous diseases [7]. This phenomenon confirms the highest activity of hydroxyl radical. 2.1. Generation of free radicals According to the aforementioned information, reactive molecules are formed as endogenous and exogenous. Each source is very important because they lead to an increase in the number of molecules and a necessity of reduction by an organism. In an aerobic organism, 90% of consumed oxygen is reduced to water, a normal physiological process, essential for life. The remaining 10% of oxygen is reduced to a superoxide anion radical or hydrogen peroxide [3]. This internal generation of free radicals is connected with normal physiological processes, which results from respiration or metabolism. This includes reactions linked to phagocytosis, prostaglandin synthesis or cytochrome P450[12]. Majority amounts of reactive molecules are produced by the electron transport chain in endoplasmic reticulum, plasmatic and nuclear membranes. Other, very important ROS producers are oxidases, which are capable of producing oxidize aldehydes, amino acids or carbohydrates [13–15]. A significant aspect of radical generation is connected with the metal-catalyzed process. Almost one-third of all proteins contain transitions metal ions. Among the metals, the most active and abundant redox-actives are iron and copper [16]. It is commonly known that the ions of metals such as Fe2+ or Cu2+ are strictly connected with proper, human brain functions. The ferrous ion has ability to reduce molecular oxygen to superoxide radicals. In the case of copper ions, these molecules can be reduced by superoxide radical forming Cu+. This new ion, reacting with hydroxyl peroxide, leads to the formation of the most active radical—hydroxyl radical OH [17]. Long-standing studies have revealed high contents of the mentioned ions and markers indicating oxidative stress in senile plaques, appearing in Alzheimer’s Disease. This phenomenon points to the significant contribution of the ions to oxidative stress and development of the neuronal disorder. In addition to endogenous sources of free radicals, equally important are exogenous factors, which causes the production of a number of these damaging molecules. These sources include cigarettes, radiation, ozone, drugs, pesticides, environmental pollutants and a many others. In many cases people do not have opportunity avoid these factors. Additional amounts of free radicals are generated during diseases and treatment. On the other hand, factors such as alcohol or cigarettes, which generate huge amounts of the harmful molecules, can be avoided. Significant problems are connected with tobacco smoke. Some of the components can produce each type of free radical, leading to oxidative damage to proteins, enzymes and DNA [18–20]. Fig. 2 shows the most important external sources of free radicals. The most important external sources of free radicals caused negative influence… Download full-size image Fig. 2. The most important external sources of free radicals caused negative influence on human organism. Apart from the negative influence on health and the human body, the reactive molecules take part in a few positive reactions such as production of immune cells to kill viruses, the ability to attack cancerous cells and can control the flow of blood [11,21]. 2.2. Oxidative stress Free radical generation is a normal process, accompanying numerous physiological reactions. Each organism counteract excess of these molecules maintaining appropriate level essential for normal functioning organism. The radicals can be scavenged by antioxidants and enzymes such as peroxide dismutase SOD, glutathione peroxide or catalase, which transfer the reactive species into stable compounds [22,23]. Unfortunately, in numerous cases the enzymes and antioxidants cannot scavenge the excess free radicals, which leads to an imbalance between the production of these reactive molecules and their elimination. This phenomenon, called oxidative stress, causes a disturbance in numerous physiological processes. In this situation, oxidative stress can be classified into two categories: acute and chronic. The first of them is connected with the temporary growth of the molecules which eventually return to normal levels. This phenomenon can result from transient diseases or drugs and does not create significance changes in human health. The second type of oxidative stress is more harmful. This type is connected with the difficulties of cells to neutralize enhanced amounts of reactive oxygen species. It can lead to the modification of a cell’s components, homeostasis, etc. Chronic oxidative stress is responsible for common degenerative diseases, such as heart disease, asthma, autoimmune and gastrointestinal diseases. This includes Alzheimer’s Disease, which will be discussed in next section of this paper [3,24]. Taking into consideration the fact that these reactive molecules take part in a chain reaction indicates that they are also dangerous. As a results of this phenomenon new radicals are created that begin a new cycle of reaction [11]. 3. Common information about antioxidants Human organisms have two defense lines counteracting the damages of oxidation: internal, from the body and external, supplied with food. The first of them arises from natural mechanisms, based on substances such as superoxide dismutase, catalase or glutathione [25,26]. Internal body sources regulating the amount of free radicals, are supported by other external substances provided by food or supplements. These substances are very important for the normal physiological functioning of an organism. Long-standing studies on natural substances, has revealed numerous compounds with antioxidant activity. According to available literature and the most recent scientific information, it can be said that antioxidants are substances that present in low concentration, compared to oxidisable substrates influential delay or inhibit oxidation of that substance [27]. These compounds react with free radicals leading to the termination of the chain reaction. The reaction relies on a donation electron from the antioxidant’s molecule to destabilize the free radical, resulting in stability of the molecules. The most important natural antioxidants are vitamin E, C, rutin and a whole group of phenols. Studies revealed that these substances can be important for therapy, as free radical scavengers and inhibitors of lipid peroxidation. More and more studies are focused on biological activities, especially free radical scavenging, of natural substances. This event is closely connected with the fact that numerous diseases result from or are connected with oxidative stress. One example can be studies on food enriched with natural antioxidants or new technological processes which provides the preservation of antioxidants in food [28–30]. In contrast to synthetic antioxidants, such as BHT or BHA, natural substances are more desired. The use of the synthetic compounds is more and more limited. Focusing on the previous mentioned antioxidants as a more essential group of compounds. Taking into consideration the fact that a lot of diseases are connected with oxidative stress, one of the main aims of scientists are new drugs based on multi-target directed ligands. These drugs can influence, not only on main cause of disease, but also, for example, on oxidative stress as accompanying cause. In the next part of the paper particular attention will be put on Alzheimer’s Disease as prime example of multi-factored disease. 4. Introduction to Alzheimer’s Disease A number of studies are focused on neurodegenerative disorders. This phenomenon results from increasing number of patients affected by diseases such as Alzheimer, Parkinson or Huntington. Particularly attention is paid to first of them. Alzheimer’s Disease is the most common type of dementia. First identification of the disorder took place one century ago but culmination of interest occurred 30 years ago and continues to the present time. According to the most recent statistics, 44 million people are affected Alzheimer or a related dementia. Alzheimer is known as multi-factor disease. Long-standing studies revealed pathological hallmarks such as decrease amount of acetylcholine, accumulation of amyloid plaques, neurofibrillary tangles or oxidative stress [31]. The risk of the disease increase with age which translates into statistics in aging population. It is worth pointing out that Alzheimer can affect people in different age groups. More and more people beyond the age of 60, suffer from mild cognitive impairment (MCI) characterized by intermediate state between normal aging and dementia. According to Padurariu et al., progression of this state is almost 50% within 4 years what leads to initial stage of AD [32]. Symptoms of AD are closely connected with rates of the disease’s development. The most common of them are changes in mood and personality, memory impairment, difficulties in planning, solving common problems and confusion with time or place [33]. These changes get worse with increasing age and lead to strong reliance of patients on other people. Solutions of the problem are prevention of the diseases such as healthy life-style (food rich in antioxidants, sport, lack of addictions), early diagnosis and effective treatment based on multi-target drugs. 4.1. Influence of free radicals on development of AD Oxidative stress is put as one of the most important causes of Alzheimer’s Disease. The most recent studies confirmed the influence of reactive oxygen species on the development of the disorders. Due to the fact that the brain is rich in easily peroxidizable fatty acids, free radicals can effectively attack these molecules leading to the formation new, harmful structures. Moreover, it was proved that amyloid peptides impact on free radical formation [34]. Numerous scientists showed correlation between free radicals and other causes of AD. Below the most significant reports are presented. Sekleret et al. [5], focused on oxidative stress status in AD patients with different stage of dementia, revealed that degree of free radicals is correlated with advance of AD. The research were performed with group of patients more than 60-years-old represent mild and moderate stage of AD. Scientists analyzed oxidative stress biomarkers. Results obtained from the FRAP method revealed a high correlation between oxidative stress marker and the stages of AD. Which indicated on increase in oxidative stress with advanced of AD. The influence of free radicals can be carried out by identification of end-products of biomolecular peroxidation [34]. This process leads to the formation of melanodialdehyde (MDA) molecules, protein carbonyls (CRBNLs), peroxynitriate and other advanced glycation products [35,36]. Significant studies were presented by Casado et al. Scientists focused on the measurement of MDA levels and superoxide dismutase, catalase, glutathione peroxidase and reductase in blood samples from patients with AD. Obtained results indicated an increasing level of MDA with age. Due to the fact that these molecules are formed during biomolecular peroxidation, the results indicate on correlation between oxidative stress and stages of Alzheimer’s Disease [37]. Another research based on MDA were performed by Padurariu et al. [32]. Similarly, to previous study, the authors took under consideration evaluation of MDA level in patients with AD. The results, lined with previous, showed positive correlation between levels of MDA and advanced in AD. There are numerous studies demonstrating results indicated on mentioned correlation [34,38–40]. Besides the negative influence of unsaturated fatty acids, free radicals affect protein, RNA and DNA. The first issue was taken by Bermejo et al. [41]. The authors presented significant MCI and AD problem, their differentiating and answering if MCI is an early stage of Alzheimer. The studies were based on correlation between protein modification with degree of oxidative stress. Numerous scientists believe that protein carbonyl groups are better marker than lipid peroxidation products. It can result from the stability of oxidized protein. Results obtained by Bermejo et al. [41] showed increased levels of the mentioned protein in plasma from patients with AD. Authors suggested that oxidative stress can be produced by accumulation of oxidative-damaged protein in plasma. They highlighted that from a chemically point of view, progression of MCI to AD is not guaranteed. Additional facilitation for harmful free radicals is a high level of iron and copper ions in the brain. These molecules are essential for a proper functioning brain but also take part in radical reactions such as Fenton [42]. This reaction generates new hydroxyl radicals which attack DNA, proteins and polyunsaturated fatty acids. Moreover, it is proved that β-amyloid, forming senile plaques, react with copper, taking part in free radical formation. Due to the connection between transition metal ions and oxidative stress, this phenomenon was carried out by numerous scientists. Smith et al [43]. focused on the examination of iron and free radical’s generation in preclinical AD. Comparison levels of iron and redox active in the cortex and area often unaffected by the AD, indicated a significant contribution of iron ions to development of the disease. Similar research based on matallo-ROS and β-amyloid were presented by da Silva and Ming [44]. The scientists considered oxidation of catecholamine and indoleamine neurotransmitter catalyzed by Cu complexes of metal-binding domains of β-amyloid. Due to disturbance of dopamine metabolism, which may be connected with Alzheimer’s, oxidation of the neurotransmitter was under consideration. Obtained results revealed that plaque-forming CuA β exhibit influential activities toward oxidation of the neurotransmitter. The authors underlined significant correlation between imbalance of neurotransmitter metabolism and β-amyloid plaques. Other very important targets of free radicals are RNA and DNA. Damage and mutation of these structures are exceptionally dangerous for the human brain. This issue was taken by Chang and Lin [45]. The aim of the study was an investigation of the relationship between RNA oxidation and neuron degeneration. Results indicated a significant influence of mRNA oxidation on a cascade of neurodegeneration, leading to the development of Alzheimer’s Disease. Gackowski et al. focused on the mentioned issue using DNA damage biomarkers [46]. Similar to previous studies, the scientists indicated a higher level of oxidative DNA damage biomarkers in patients with dementia. Numerous other studies revealed an influential connection between Alzheimer’s disease and damage caused by free radicals [47,48]. One of solutions to the problem could be antioxidants contributing to the natural defense body’s mechanisms. 4.2. The influence of antioxidants on Alzheimer’s Disease A large number of reports show a role of oxidative stress in Alzheimer disease (AD). Some recent evidence even suggests that this phenomenon is an early event and may play a functional role in the pathogenesis of this disease. Chronic, low-dose antioxidant therapy is both safe and effective in lowering the accumulative damage of oxidative stress products (Table 1) [49]. Before starting any antioxidant therapy, it is very important to have clear information on the endogenous antioxidant levels. The most important consideration is the need to monitor the therapy. Table 1. Antioxidants interventions studied for Alzheimer’s disease. Antioxidant Mechanism of action Outcome Ion chelator (desferrioxamine) Reduces formation of free radicals Reduction in the rate of decline of daily living skills [54] Caloric restriction Prevents and reduces formation of free radicals Caloric restrictions correlated with attenuation of age-related deficit in learning and memory [55] Higher amount of fish and vegetables lead to reduce the risk of AD [58] Lack of significant influence of amount of carbohydrates in diet on development of neurodegenerative disorders [59] Diet rich in fruits and low amount of saturated fats influences on better cognition [60] Vitamin E (tocopherol) A lipid-soluble antioxidant; prevents the in-vitro oxidation of the membrane lipids and the accumulation of oxidative metabolites induced by Aβ peptide neurotoxicity [61,62] affects the expression of genes that are involved in the clearance of Aβ [63] Administration of vitamin E correlated with cognitive decline [66]; long-time supplementation of vitamin C and E, results in a better cognitive condition and prevents brain oxidative damage [67]; reduction of cases of Alzheimer’s Disease, especially in smokers [68,69]; high doses of vitamin E had no benefit in subjects with a clinical diagnosis of mild cognitive impairment (MCI) [71]; no association between supplementary vitamin E intake and a decrease in the risk for AD [73] Vitamin C A water-soluble antioxidant; an inhibitor of lipid peroxidation, acts in bloom and plasma [137] Reduced risk for developing AD during supplementation the combination of vitamin E and vitamin C [31,74] Glutathione (GSH) and N-acetyl-l-cysteine (NAC) GSH—the most widespread antioxidant in the brain, reacts with nucleophilic compounds and free radicals; it is able to maintain reduced forms of other antioxidants [57] The ratio GSH/GSSG can be used as indicator of neurodegenerative [78] NAC increases glutathione levels and directly inhibited inflammatory factor NF-κB and blocked production of nitric oxide from inducible nitric oxide synthase and inflammatory cytokines [88] Late-stage AD patients supplemented with NAC, demonstrated significantly improved performance [89] Co-enzyme Q10 (CoQ10, ubiquinone), Prevents protein, lipidic and DNA oxidation, especially mitochondrial DNA [66,67];protects neuronal cells against amyloid beta toxicity [93] Large doses of CoQ10 may slow the cognitive decline in AD [96] Uric acid (UA) Is responsible for neutralizing a large number of the free radicals in human blood [93] Prevent ischemia-induced oxidative neuronal damage in rats [51] Vitamin B12 Antioxidant acts mainly in nerve cells and red blood cells [137] Increases choline acetyltransferase activity in cholinergic neurons in cats [137]; improves cognitive functions in AD patients [137] α-Lipolic acid (LA) Increases the production of acetylcholine, recycles other antioxidants, chelator of redox-active metals [137] Decreased expression of lipid peroxidation markers of oxidative modification but not β-amyloid load within the brains in mice [137] Plant’s polyphenolic compounds Are responsible for neutralizing a large number of the free radicals in human blood, increase the intracellular levels of antioxidant enzymes, decrease of Aβ production and/or toxicity as well as oxidative damage induced by Aβ [98,103,105,106] Functional drink rich in polyphenols decreases homocysteine plasmatic concentrations in Alzheimer’s patients, reduces the effects of inflammation and cardiovascular risk [97,98]; grape-derived polyphenols influences on AD amyloid neuropathology [99]; moderate consumption of red wine reduces attenuate AD amyloid pathogenesis and cognitive deterioration in preclinical models of AD [100] and the prevalence of Alzheimer disease [101]; neuroprotective effects of the Alpinia oxyphylla alcoholic extract, protects mice from Aβ1-42-induced memory neuron impairment, as well as from Aβ1-42-induced learning and memory impairments in AD mice, attenuates the neuronal damage and apoptosis in the frontal cortex and hippocampus in mice [102,103]; moderate neuroprotective effects of Ginkgo biloba [105,106,112,113], but its clinical relevance is difficult to evaluate [117] Caffein Inhibits Aβ production and reduce brain Aβ levels [118] Decreased Aβ production and accumulation, attenuated ROS and 8-Iso-PGF2α levels, and reduced glutathione depletion, and protection against cholesterol-induced ER stress in cholesterol-fed rabbit model [118] Melatonin Stimulates the expression and activity of glutathione peroxidase, superoxide dismutase, and NO synthetase and contributes to the reduction of oxidative damage in cells [139] Improved learning and memory deficits, increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease [124] Various compounds have the ability to quench free radicals using three mechanisms: prevention (or reduction) of the formation of free radicals, reacting with them directly or limiting the extent of the damage by detoxification. The first group includes, modulators of superoxide dismutase (SOD), catalase, and glutathione peroxidase, iron chelators and caloric restriction. SOD, catalase, and glutathione peroxidase are the three primary enzymes involved in direct elimination of active oxygen species whose activity is reduced with age and in some pathological conditions [50]. Overexpression of human Cu–Zn SOD in transgenic mice showed reduced oxidative damage in the brain and improved cognitive functions. Conversely, and overexpression of peroxidase also showed antioxidative function and reduced homocysteine induced endothelial dysfunction [51]. Amyloid-beta (Aβ) plays an important role in the pathogenesis of AD [52,53]. The accumulation of Aβ stimulates glial cell activation, resulting in enhanced production of a variety of oxidative and pro-inflammatory mediators, which may play an important role in neuronal dysfunction in Alzheimer’s disease. Therefore, to safely prevent or even remove the toxin, Aβ peptide is considered to be an effective method for the prevention and treatment of AD [31]. Because copper and zinc play a major role in Aβ toxicity and nerve cell death via ROS generation, chelator therapy is, in effect, an antioxidant [51]. McLachlan and coworkers conducted studies to investigate whether the progression of dementia could be slowed by the desferrioxamine—trivalent ion chelator [54]. 48 patients with probable AD were divided into three groups. The first group was administered desferrioxamine (250 mg per day, intramuscularly, 5 days per week, for 24 months). The second – oral placebo and the third – no treatment. Desferrioxamine treatment led to a significant reduction in the rate of decline of daily living skills. The authors demonstrated this class of compounds to be effective in preventing AD progression. Numerous scientists are focused on the dependency of Alzheimer’s diseases and diet, including calories and amount of saturated and unsaturated fatty acids. Studies concerning caloric restriction in rodents and monkeys showed an attenuation of age-related deficits in learning and memory and reduces the incidence of age-related disease [55]. The mechanism of the beneficial effect of caloric restriction is not clearly understood, yet. In the case of humans, a low daily calorie intake is associated with a reduced risk for Alzheimer disease [56]. Luchsinger et al. [57]. based on information from WHICAP, indicated a dependence between risk of AD and food calories. The author underlined that persons in the fourth quartile of caloric intake had a higher risk of Alzheimer’s. The same authors paid attention to saturated and unsaturated fats. It is commonly known that omega-3 (polyunsaturated fatty acids) are very important for correct functioning of our organism, especially the cardiovascular and neuronal system. Luchsinger et al. indicated a positive impact of higher amount of fish and vegetables in our diets, which potentially, should reduce the risk of AD. Other, very interesting results were presented by Navrátilová et al. [58]. Their scientific work was focused on the effect of nutrition support. The studies included 100 patients with AD, who were divided into two groups: receiving nutrition supplements and without supplements while continuing ordinary food. The results were compared at the beginning of the study and after one year. Obtained results indicated on deterioration of mental function in patients without supplementation. In the case of patients with supplementation (+651 kcal) development of AD was lower in comparison to the second group of patients. Similarly, studies were performed by Navarro-Meza et al. [59]. The authors presented results obtained for the influence of dietary fat and vitamins on the development of neurodegenerative disorders in patients from Mexico. The studies involved 20 patients with AD and PD (Parkinson disease) and a control group (41 people without degeneration) from 50 to 89 years. Patients consumed calories equal to 6786 kJ per day and the daily average intake of kcal consumed according to macronutrients was determined. Obtained results indicated a lack of statistically significant dependence between studied groups for carbohydrate and macronutrient. The authors underlined the lack of important influence of caloric diet on neurodegenerative development in patients from the rural regions of Mexico. They suggest that this phenomenon is connected with other factors such as physical inactivity. The influence of caloric diet and components such as carbohydrates or fats are constantly studied. Each of the research indicate on different results. Interesting studies were performer by Luchsinger et al. whose another results were presented above [60]. In this study 980, 65 year-olds or older individuals took part. Every day total caloric diet (in kcal) was measured. In the case of macronutrients (fats, protein, carbohydrates) these components were calculated in grams per day and adjusted according with linear regression models. Daily intake was: 1267 kcal including: 38 g fats, 60 g protein and 176 g carbohydrates. Each of the groups was divided into two parts: lowest and highest quartiles. Results indicated better cognition in the case of participants whose diet was rich in fruit, vegetables with lower amount of saturated fats and complex carbohydrates. All things considered, it can be said that a dependence between caloric diet and Alzheimer disease is hard to explicitly explain. Obtained results are closely connected with factors such as social status or education level of examined patients. In some cases, according to author’s theory of AD factors, higher caloric intake can be connected with lower education. In the future, more in-depth studies should be performed. The main compounds, known as good antioxidants are: tocopherols, ascorbate, glutathione, ubiquinone, uric acid, polyphenols, alkaloids, terpenoids, carotene and other plant-derived substances as well as retinol and other polyenes, selenium-containing compounds, estrogen, serotonin [51]. Vitamin E (tocopherol) is a major lipid soluble antioxidant, that prevents the in-vitro oxidation of the membrane lipids and the accumulation of oxidative metabolites induced by Aβ peptide neurotoxicity [61,62]. In addition, vitamin E affects the expression of an array of genes that are directly or indirectly involved in the clearance of Aβ [63]. Vitamin E may cross the blood brain barrier (BBB) and accumulate at therapeutic levels in the central nervous system, where it is able to lower the lipid peroxidation process [64]. In the study, performed in large groups (>4000 of elderly patients), decreased circulating levels of vitamin E are consistently associated with decreasing memory levels, while a levels of vitamin A, C, β-carotene, and selenium do not have this relationship [65]. The examination of almost 3000 patients aged 65–102 years, showed that the administration of vitamin E, but not C, is inversely correlated with cognitive decline [66]. Another experiment, including almost 15,000 women (70–79 years old), indicated that long-time supplementation of vitamin C and E, results in a better cognitive condition and prevents brain oxidative damage [67]. The Rotterdam study results (more than 5000 patients over 6 years) have proven, that dietary intake of vitamin E is associated with the reduction of cases of Alzheimer’s Disease. This association is more evident in individuals who are current smokers, but is not influenced by the apolipoprotein E genotype [68,69]. The data, for patients with AD of moderate severity, receiving a high dose application of vitamin E (2000 IU/day, 2-year), proved a significantly delay in the time to all primary outcomes (e.g., death, loss of ability to perform basic activities, institutionalization and severe dementia). However, it did not influence the rate of decline or cognitive functions [70]. Another report showed that the same high doses of vitamin E had no benefit in subjects with a clinical diagnosis of mild cognitive impairment (MCI) [71]. In a recent publication, the same authors showed that in certain patients, percentage changes in the volumes for hippocampus and entorhinal cortex, are less evident in the group receiving the vitamin E than in the placebo [72]. In the study conducted by Luchsinger et al., there was no association between dietary or supplementary vitamin E intake and a decrease in the risk for AD [73]. While the beneficial effect of a reduced risk for developing AD is seen in the combination of vitamin E and vitamin C [74]. Differing results of experiments arise from the fact that no data is available on some important parameters that provide necessary information when an antioxidant therapy is administered; drug level monitoring (in the serum and brain) and a surrogate marker for the in vivo therapeutic effect of the drug of interest [75]. This goal can be achieved only if we monitor the antioxidant substance levels, and, most importantly, the in vivo antioxidant effect. This is achieved by measuring any of the several available surrogate markers of oxidative stress before starting and during the treatment. There is a long list of markers, which include lipid, DNA, and protein oxidation, of oxidant stress-mediated injury that have been reported to be elevated in the AD brain. Considering the complexity of the redox system in vivo, in certain cases, a combination of antioxidants would be preferable to a single antioxidant. For example, an application of vitamin E together with vitamin C [31], which has the ability to scavenge superoxide and hydroxyl radicals as well as lipid hydroperoxides [76]. The failures in many clinical trials likely arose from starting the therapies in the late stages of AD, not monitoring drug levels and markers and underutilizing a multi-antioxidant approach that covers both lipophilic and hydrophilic areas of the cell [77]. The most widespread antioxidant in the brain, glutathione (GSH), is found in millimolar concentrations in a large number of cells [78]. Reduced GSH reacts with nucleophilic compounds and free radicals, forming oxidized glutathione (GSSG). Moreover, it is able to maintain reduced forms of other antioxidants, such as vitamin C and E [61]. GSH levels are decreased with age and in diseases linked with oxidative stress [26]. Decreased levels of glutathione (GSH) in cortical areas and the hippocampus has been found to be a relevant feature in AD patient [8]. Thus, the ratio GSH/GSSG can be used as indicator for oxidative status in vivo in neurodegenerative disorders, such as AD [78]. MCI is often considered to as a transitional period between normal cognitive aging and probable Alzheimer’s disease. Many patients with amnestic MCI develop AD [79]. Oxidative stress conditions in early AD are already present in MCI, and the decreased antioxidant activity, particularly glutathione, may initiate the progression to AD [80]. The studies clearly confirm that a decrease of GSH, over time, is a major contributor to the progression of MCI to AD. Glutathione is comprised of the amino acids glutamate, cysteine, and glycine. Glutamate and glycine are found in millimolar concentrations, whereas free cysteine is limited, with most non-protein cysteine being stored within GSH. Two enzymes are involved in the synthesis of reduced glutathione: γ-glutamylcysteine ligase and gluthathione synthase [77]. Because the physiological amount of brain-resident cysteine limits the formation of GSH, researchers are studying the possibility of increasing cysteine levels in the brain as an indirect way to increase the levels of GSH. In particular, N-acetyl-l-cysteine (NAC) is known to directly increase brain cysteine levels, permitting for an increased biosynthesis of GSH in the brain and periphery [81]. NAC crosses the blood brain barrier (BBB) [82], increases GSH levels and directly interacts with free radicals. Intraperitoneal injection of NAC to rodents increased GSH in brain, synaptosomes and offered protection against peroxynitrite, hydroxyl radicals, acrolein, and oxidative stress induced by 3- nitro-propionic acid [81,83]. NAC also enhanced neuronal survival in the hippocampus after ischemic–reperfusion [84]. Pretreatment with NAC in mice receiving intracerebroventricular injections of Aβ, had improved learning and memory [85]. NAC also increased GSH levels, protected against Aβ-induced protein and lipid peroxidation while decreasing acetylcholine levels and choline acetyltransferase activity [85]. NAC may play a role in amyloid precursor protein (APP) processing, Aβ formation as well as decrease oxidative stress in vivo in mice brains [86]. During the progression of AD, neuroinflammation frequently occurs. Astrocytes are the main supplier of GSH to microglia and neurons. During chronic inflammation and oxidative stress, astrocytes release toxic inflammatory mediators and free radicals, accelerating neurodegeneration [87]. NAC increases glutathione levels, but also directly inhibited inflammatory factor NF-κB and blocked production of nitric oxide from inducible nitric oxide synthase and inflammatory cytokines [88]. Given the multi-faceted way NAC is capable of modulating AD, patient supplementation with NAC has been introduced. Late-stage AD patients supplemented with NAC, over a six-month period, not only tolerated the treatment well, but also demonstrated significantly improved performance [89]. γ-Glutamylcysteine ethyl ester (GCEE) introduces the precursor for the last step in GSH synthesis, guiding cysteine directly toward GSH synthesis in the brain and periphery and avoiding the feedback inhibition of γ-glutaminecysteine ligase. GCEE is able to increase brain and mitochondrial GSH levels and protect synaptosomes, neuronal cells, and mitochondria against peroxynitrite damage [90]. and DNA fragmentation [91]. Moreover, GCEE may react directly with ROS. Co-enzyme Q10 (CoQ10, ubiquinone), is a lipophilic antioxidant endogenously synthesized and is able to efficiently prevent protein, lipidic and DNA oxidation, especially mitochondrial DNA. CoQ10 is produced in most cells and its involvement in ATP production is thought to be beneficial to ameliorate impaired mitochondrial function and oxidative damage [92,93]. CoQ10 preserves mitochondrial membrane potential during oxidative stress and protects neuronal cells against amyloid beta toxicity [94]. Data from the study showed that the intake of large doses of CoQ10 may slow the cognitive decline in AD. However, co-enzyme Q10 has at least two limitations—it is unable to cross the BBB [95] and it is entirely dependent on the functioning of the electron transfer chain [96]. Uric acid (UA), a compound having antioxidant, neuroprotective and anti-inflammatory activities, is one the of most important antioxidants in human biological fluids. Patients with Alzheimer’s disease have a significantly reduced level of UA. This compounds is responsible for neutralizing a large number of the free radicals in human blood by eliminating superoxide, peroxynitrite and hydroxyl radicals, and preventing the oxidation of vitamin C [93]. UA was also found to prevent ischemia-induced oxidative neuronal damage in rats. In addition, it is more effective than either vitamin C or E in protecting against glutamate neurotoxicity [51]. Plant compounds, such as flavonoids, phenolic acids, alkaloids, terpenoids, carotene etc. are one of the most important classes of exogenous antioxidants that are present in human diet. Therefore, antioxidants from natural extracts are an important group in prevention and treatment of Alzheimer disease. Morillas-Ruiz et al. [97] in their study, determined that regular ingestion of a functional drink, rich in antioxidant polyphenols from apples and lemons concentrate juice and green tea extracts (200 mL/person/day for 8 months) may decrease homocysteine plasmatic concentrations in Alzheimer’s patients, especially in the moderate phase. The study involved 100 subjects (52 of control group, 24 AD patients in initial phase and 24 AD patients in moderate phase) (Mini-Mental State Examination scores between 14 and 26, inclusive). Fasting plasma concentrations of homocysteine, folate and vitamin B12 were measured before and after the ingestion of the drink. In AD blood levels of homocysteine may be increased and it contributes to disease pathophysiology by vascular and direct neurotoxic mechanisms [98]. Higher homocysteine levels are observed more frequently in the AD moderate phase patients than in the AD initial phase patients and in the control group. The results suggest that polyphenol beverages can reduce the effects of inflammation and cardiovascular risk associated with AD. Probably, due to the ingestion of antioxidant beverage, lower levels of plasmatic thiol groups of homocysteine are found, (they undergo auto oxidation in plasma), producing less reactive oxygen species, so oxidative stress and cell damage will be lower. Other research proved, that grape-derived polyphenols may beneficially influence AD amyloid neuropathology [99]. Moreover, moderate consumption of red wine (which contains polyphenols) reduces attenuate AD amyloid pathogenesis and cognitive deterioration in preclinical models of AD [100] and the prevalence of Alzheimer disease [101]. The study conducted by Shi et al [102]. explored the neuroprotective effects of the Alpinia oxyphylla alcoholic extract (containing e.g., 5-hydroxymethyl furfural, phenolic acids). This extract (180 mg/kg, 360 mg/kg) significantly protected mice from Aβ1-42-induced memory neuron impairment, as well as from Aβ1-42-induced learning and memory impairments in AD mice (in vivo behavioral testing). Moreover, it was able to attenuate the neuronal damage and apoptosis in the frontal cortex and hippocampus in mice. In addition, the inhibition of β-secretase and the level of Aβ1-42 are also involved in the action mechanisms of A. oxyphylla extract in this experimental model. Described properties are determined by crossing the blood–brain barrier by small molecules and phenolic acid (with low molecule weight and low numbers of hydrogen bonding), contained in extract of A. oxyphylla. Utility of compounds extracted from A. oxyphylla used in treatment of Alzheimer’s disease was confirmed Liu and coworkers [103]. They separated 5-Hydroxymethylfurfural (5-HMF) from A. oxyphylla fruits. In order to identify a potential therapeutic agent, the neuroprotective effects of 5-HMF on impairment of cognition and memory function induced by intracerebroventricular (ICV) injection of Aβ1-42 were investigated in vivo. The mice were treated with 5-HMF at dose of 15 μg/kg and 150 μg/kg for five consecutive days after intracerebroventricular Aβ1-42 injections. The results showed that 5-HMF significantly ameliorated learning and memory impairment evaluated by the locomotor activity, Y-maze test, and Morris water maze test. Furthermore, 5-HMF significantly inhibited the β-secretase activity, decreased the content of Aβ1-42 and malondialdehyde (MDA), and increased the antioxidative enzyme activities, including superoxide dismutase (SOD) and glutathione peroxidase (GPx). Studies have also shown that 5-HMF could mitigate the degree of neuronal damage. These results suggested that A. oxyphylla extract and its important constituent—5-HMF might offer a useful therapeutic choice in either the prevention or the treatment of Alzheimer’s disease. Ginkgo biloba extract is well absorbed by oral route: the bioavailability for flavonol-glycosides is >60%, for ginkgolides >98% and for bilobalide ∼70% [104]. Ginkgo biloba’s extracts contain several active compounds, including flavonoids, terpenes, organic acids and polyphenols, the most important are flavonol-glycosides (quercetin, kaempferol and isorhamnetin derivatives) and terpene-lactones. Terpene-lactones are capable to cross the rat blood–brain barrier [97]. Several preclinical studies in rodents put forth the neuroprotective role of Ginkgo biloba, mainly due to its ability to prevent free radical induced damage, increase the intracellular levels of antioxidant enzymes and restore calcium homeostasis [105,106]. Ginkgo biloba inhibited the formation of Aβ fibrils in a neuroblastoma cell line overexpressing an AD-associated double mutation [107]. Furthermore, 10–100 μg/ml dose dependently counteracted Aβ-induced toxicity in rat hippocampal primary cultured cells [108]. The antioxidant effect of seemed to be attributable to the flavonoid fraction rather than the terpene-lactones fraction [108]. Stackman et al. have reported that mice treated with Ginkgo biloba showed cognitive improvement without any effects on Aβ [109]. The efficacy of Ginkgo biloba against free radicals demonstrated by improved survival and inhibited ROS and RNS accumulation in rat primary mixed hippocampal cell cultures exposed to sodium nitroprusside [110] or in neuroblastoma cell line overexpressing an AD-associated double mutation treated with hydrogen peroxide [111]. Although these are promising preclinical evidences, the efficacy of Ginkgo biloba was not confirmed in AD patients. Clinical trials demonstrated a slight improvement in cognitive functions in individuals suffering from mild-to-moderate AD and treated with Ginkgo biloba 120–240 mg/day for a short (12–24 weeks) or long time (up to 52 weeks) [112,113]. On the other hand, other clinical trials were not able to confirm its efficacy to ameliorate cognitive function in MCI and mild-to-moderate AD patients [114–116]. A systematic review confirmed that the neuroprotective effects of Ginkgo biloba are moderate, but their clinical relevance is difficult to evaluate [117]. The positive effect on the decreasing of Aβ production and/or toxicity as well as oxidative damage induced by Aβ have moreover: caffeine [118], curcumin [119], silibin [120], Mito Q, Szeto Schiller peptide 31 [121], estrogen, selegiline [122], acetyl-l-carnitine [93] and melatonin [123–125]. The most established approach for the treatment of AD is the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Several AChE inhibitors are used to attenuate the symptoms related with this disease, however, some of these shows several side effects [126]. Custódio et al. [127]. reported the in-vitro antioxidant and inhibitory activities of methanol extracts of cork oak (Quercus suber) against acetylcholinesterase and butyrylcholinesterase. The extracts at the concentrations of 1 and 10 mg/mL were evaluated for their inhibitory activity against AChE and BuChE. Results were expressed as percent inhibition relative to a control containing DMSO instead of extract. Galanthamine was used as reference at a concentration of 1 mg/mL. The most significant effects on cholinesterase activity inhibitory as well as antioxidant were obtained for the methanol leaf extract (concentration of 1 mg/mL), containing: phenolics, tannins and flavonoids. Significant anti-acetylcholinesterase, anti-butyrylcholinesterase and antioxidant activities possess also Atriplex laciniata L. methanolic extract enriched with phenolic and flavonoid contents [128]. The main objective of this investigation of another study [129] was to evaluate AChE inhibition and antioxidant activity of chloroformic, n-hexanoic, ethanolic and hydro-alcoholic extracts from Ipomoea aquatica Forsk. All the four extracts were examined for in-vitro anti-cholinesterase (by Ellman’s method), antioxidant activity and hydrogen peroxide radical scavenging assay (by DPPH and Hydrogen peroxide radical scavenging assay). Results obtained from the study clearly demonstrate that all four extract has shown promising significant activity in both the AChE inhibition and anti-oxidant activity. However, hydro alcoholic extract reveals the best potential, because of the highest content active chemicals which possess antioxidant and also has anticholinesterase property. Zhang et al. [130]. examined extract of the leaves of Acanthopanax henryi, containing caffeoyl quinic acid derivates and flavonoids and their antioxidant, as well as acetyl cholinesterase inhibitory activities. Anti-oxidant activity of the isolated metabolites was evaluated by free radical scavenging (DPPH, ABTS radicals) and superoxide anion scavenging. The results showed that di-caffeoyl quinic acid derivates had stronger antioxidant activity than positive controls (ascorbic acid, trolox and allopurinol), while quercetin, 4-caffeoyl-quinic acid and 4,5-caffeoyl quinic acid were found to have strong acetyl cholinesterase inhibitory properties. Likewise, a crude methanol extract and four fractions (petroleum ether, chloroform, ethyl acetate and aqueous) from the leaves of Aegle marmelos were assessed for AChE inhibitory activity and antioxidant properties [131]. Among the different extracts tested, the ethyl acetate fraction exhibited the maximum inhibition of AChE activity and radical scavenging ability, because of highest contents of phenolics and flavonoids. The antiradical activity of the ethyl acetate fraction appeared to be similar to that of the reference standard butylated hydroxytoluene and catechin used in this study. In addition, the ethyl acetate fraction displayed higher inhibition of brain lipid peroxidation. Extracts from Berberis aetnensis C. Presl. and Berberis libanotica Ehrenb. ex C.K. Schneid. Roots exhibit ability to inhibit acetylcholinesterase, butyrylcholinesterase and antioxidant properties [132]. With respect to antioxidant effects B. libanotica showed greater activity rather than B. aetnensis. Extracts, fractions and isolated compounds inhibited AChE and BChE to various degrees. The methanol fractions of B. aetnensis and B. libanotica exhibited the strongest AChE inhibitory activity. Both species are characterised by the presence of the alkaloids berberine and palmatine as main constituents. Berberine was more potent of palmatine against AChE. Findings have shown the anti-Alzheimer’s potential effect of the hydroalcoholic extract of Bouvardia ternifolia[133], that could be attributed to its contents of polyphenols, coumarins, and triterpenes. Phytochemical analysis showed the presence of 3-O-quercetin glucopyranoside, rutin, ursolic and oleanolic acid, 3-O-quercetin rhamnopyranoside, chlorogenic acid, and scopoletin. Results demonstrated that B. ternifolia extract and ethyl acetate fraction induced anti-inflammatory effects, reducing inflammation by >70%, while antioxidant test revealed significant IC50 values for flavonoid content fraction (30.67 ± 2.09 μg/ml) and ethyl acetate fraction (42.66 ± 0.93 μg/ml). The maximum inhibition of acetylcholinesterase was exhibited by scopoletin content fraction (38.43 ± 3.94%), while ethyl acetate fraction exerted neuroprotective effect against b-amyloid peptide (83.97 ± 5.03%). The main objective of the investigation conducted by Alama and Haque [134] was to evaluate antioxidant and anticholinesterase activity of crude methanolic extract of the seeds of Celastrus paniculatus along with its organic soluble fractions. All extracts had antioxidant properties, but ethyl acetate fraction showed the highest DPPH free radical scavenging activity, inhibiting activity of authentic peroxynitrite and inhibition of total reactive oxygen species. All extracts exhibited statistically significant cholinesterases (AChE and BChE) inhibitory effects. The third group able to detoxify the formed ROS adducts and repair the damage they produce includes: tenilsetam, arnitine, creatine, lipoic acid, ubiquinone and idebenone, etc [51]. Many efforts are directed not only toward novel potential Alzheimer disease-modifying treatments and interventions, but also toward developing an alternative symptomatic and supportive treatments. Examples of these efforts include medical foods [135–137], complementing ketone bodies as alternative energy source to neurons, precursors which could enhance synaptic function and antioxidants play a role in decreasing of oxidative stress. Concept and evidence supporting use of diets is being reviewed. An example can be Mediterranean diet, a possible alternative to medical foods that, if implemented correctly, may have lower costs, fewer side effects and stronger epidemiological health outcomes [135,138]. 5. Conclusions Even if some of the presented results do not indicate an explicit correlation between level of free radicals and development of Alzheimer’ Disease, taking into consideration this phenomenon is particularly significant. An increasing number of scientists are focused on multi-target directed ligands, which can act toward a few causes of AD. One of the most important feature of the new active substances is antioxidant activity. It is closely connected with numerous studies indicated on heightened amount of oxidative stress in patients with AD in comparison to health organisms. It can be validated by positive effect of substances based on strong antioxidants on patients with MCI and AD. All things considered, it can be said that free radical scavengers are one of the solution toward Alzheimer’s Disease. 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