Alzheimer's Disease Pathology and Oxidative Stress: Possible Therapeutic Options

Tiwari SC^* and Soni RM

Department of Geriatric Mental Health, King George’s Medical University UP, India

Corresponding Author:

Dr. S. C. Tiwari
Professor and Head, Department of Geriatric Mental Health
King George’s Medical University UP, Lucknow: 226003, India
Tel: +91-9415011977
E-mail: sarvada1953@gmail.com

Received date: August 06, 2014; Accepted date: October 10, 2014; Published date: October 20, 2014

Citation: Tiwari SC, Soni RM (2014) Alzheimer’s Disease Pathology and Oxidative Stress: Possible Therapeutic Options. J Alzheimers Dis Parkinsonism 4:162. doi: 10.4172/2161-0460.1000162

Copyright: © 2014. Tiwari SC et al.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Alzheimer’s disease (AD) is one of the most common causes for the development of Dementia in the elderly. In past two decades there has been abundant research in pathogenesis of AD and possible prevention and treatment. Research evidences have suggested the major role of oxidative stress in the pathogenesis of AD. Sources of this stress are disruption of homeostasis of metals, mitochondrial dysfunction, genetic mutations, β Amyloid accumulation, hyperphosphorylation of tau and inflammation. Oxidative damage found in AD occurs as a result of advanced glycation end products, nitration, lipid peroxidation adduction products, carbonyl modified neurofilament protein and free carbonyls. All the products, discussed above have been considered as blood biomarkers for early diagnosis of AD. Various antioxidant therapies have been identified and studied for prevention and possible treatment of AD, based on role of oxidative stress in pathogenesis of AD. In this review we briefly discuss about the sources of oxidative stress and pathogenesis of AD, along with various newer and older antioxidant therapeutic options.

Keywords

Alzheimer’s disease; Oxidative stress; Blood biomarkers; Antioxidant therapies.

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease which causes dementia in the elderly, characterized by the gradual deterioration of the memory and other cognitive functions and it passes through various stages and finally results in complete incapacity and death of the patient within 3 to 9 years [1]. Increasing age is a major risk factor for sporadic forms of AD. Population of the elderly is increasing worldwide and therefore the prevalence of AD. AD has become one of the leading causes of disability and death among the elderly [2-5]. There has been abundant research in AD disease in the past few decades, but the exact cause and pathogenesis of AD are not completely understood, and right now, we do not have effective treatment options for the disease. Etiology of the AD is multifactorial and quite a mysterious phenomenon. Research in the genetics and molecular biology has explained some of the underlying mechanisms for the pathologies found in the AD. Research in the genetics has identified the genes involved in the AD.

Table 1: Genes involved in Alzheimer’s disease [6-9].

Apart from these, a2-macrogobulin gene located on chromosome 12 [10] and other unidentified genes also determine the susceptibility in late onset forms and sporadic cases.

Amyloid hypothesis is another causative mechanism in AD. Principle hallmark of the AD neuropathology are: Senile plaques (typically composed of amyloid protein) and neurofibrillary tangle (mainly composed of tau protein). Both of these are the result of amyloidogenesis and specifically, formation and deposition of a long β-Amyloid peptide (Aβ) of 42 or 43 amino acids (Aβ42). Various mutations have also been described on the APP (Amyloid precursor protein); PS I (Presenilin-I) or PS II (Presenilin-II) genes all causes increase production of this long β-Amyloid peptide [11]. In addition to this, cytokines, transforming growth factor β1, interleukin1 and various complement factors are also involved in the process of amyloidogenesis [12,13].

Amyloid hypothesis explains the neuropathology to some extent but it does not explain the relation between amyloidogenesis and development of neurofibrillary tangle. There is a question about how this neurodegeneration and neuronal death occur? It seems that free radicals probably responsible for these processes. The free radical hypothesis of aging was proposed years ago, says that age related accumulation of the reactive oxygen species (ROS) results in damage to major components of the cell: nucleus, mitochondrial DNA, membranes, and cytoplasmic proteins. Most neurodegenerative diseases including AD are the result of imbalance between free radical generation and free radical scavengers [14-16]. The human Brain consumes large amount of oxygen compared other organs, like it weighs only 2% of the body weight but consumes about 20% oxygen supplied by the respiratory system [17]. This high energy consumption of the brain suggests that it is more susceptible to oxidative stress. Because neuron is the basic functional unit of the brain, it has higher metabolic rate, and therefore more vulnerable to oxidative damage [18]. Other reasons for their vulnerability are; low content of glutathione, a natural antioxidant [19] and high amount of polyunsaturated fatty acids in their membranes [20]. Age is the key risk factor for the AD because free radical injury to the neurons can gradually accumulate over the years [21]. Such general findings suggest that free radical injury is associated with many age related pathologies including AD and other neurodegenerative diseases [22].

Oxidative damage and sources of oxidative stress in AD

Under normal physiological conditions, there is balance between free radicals and antioxidants, which is disturbed in pathological conditions. Oxidative damage occurs when the reactive oxygen species are in excess of cellular antioxidant defences. Oxidative damage found in AD occurs as a result of advanced glycation end products [23-26], nitration [27,28], lipid peroxidation adduction products [29,30], carbonyl modified neurofilament protein and free carbonyls [31,32].

Research in molecular biology has suggested that mitochondrial dysfunction [33-36], metal accumulation [33,37,38], hyperphosphorylated Tau [39,40], inflammation[41,42], β-Amyloid (Aβ) accumulation [33,35,36] are responsible for the oxidative stress and damage. Oxidative stress occurs because the components of the antioxidant system like superoxide dismutase (SOD) in mitochondria and cytosol, glutathione peroxidase, and catalase are deficient or destroyed. As a result the clearance of the free radicals reduces and oxidative stress arises [43-45]. Apart from this oxidative stress also contributes to Aβ accumulation and tau hyperphosphorylation, which suggests that it plays an important role in pathogenesis of AD [33,36,46] and it can be biomarker and possible treatment target for AD [46-48].

Lipid oxidation

Neurons are very rich in phospholipids, and are very important for the process of neurotransmission, neuronal interactions and cognition. These phospholipids have high proportions of PUFA, especially docosahexaenoic acid and arachidonic acid. It has been found that when free radical production increases, PUFA content of the brain gradually decreases [49,50]. In addition, the products of lipid peroxidation are very unstable and automatically converted into malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), ketones, epoxides, and hydrocarbons in the presence of iron [49]. Many studies have confirmed that patients with AD and mild cognitive impairment have increased levels of MDA and 4-HNE in their brains [51-53]. Isoprostanes (F2-IsoPs) are produced from arachidonic acid via esterification. Levels of F2-IsoPs and F4-IsoPs have been found to be increased in cerebrospinal fluid (CSF) in patients with AD and mild cognitive impairment (MCI) [54-57].

Protein oxidation

As a result of oxidative damage proteins are converted to protein carbonyls, levels of which are high in brains of AD patients [53]. Tyrosine is converted to 3-nitrotyrosine and dityrosine after reaction with reactive oxygen and nitrogen species. The level of 3-nitrotyrosine residue in the CSF is negatively correlated with mental status examination score [58,59]. One study has shown that levels of total protein nitration in the inferior parietal lobule and in the hippocampus in the patients with MCI are much higher than those in healthy control subjects, which shows that protein nitration starts early in the AD pathology.

Nucleic acid oxidation

8-hydroxydeoxyguanosine (8-OHdG) is formed due to DNA oxidation. The level of 8-OHdG in mitochondrial DNA in the parietal cortex of the AD patients is increased significantly as compared to the controls [60]. The level of 8-OHG is found to be increased a decade before the appearance of neurofibrillary tangles (NFTs) and Aβ plaques in the brain of AD patients. DNA oxidation can also be measured by DNA strand breakage. One study has reported that the level of DNA strand breakage in cerebral cortex of AD patients is twice as compared controls [61].

All the products, discussed above have been considered as blood biomarkers for early diagnosis of AD [49]. It requires further research to establish their efficacy as early biomarkers.

The Role of Metals in AD

From the beginning, transition metals like copper, iron, aluminum, zinc etc. are the target for the research in AD pathology. These metals play critical role in the production of the free radicals. Areas of brain (hippocampus, amygdala etc.) involved in the AD pathology have shown abnormal levels of these metals [62]. Oxidative stress is produced when these metals interact with Aβ.

Iron is involved in Fenton’s and Haber-Weiss’s type of reactions and result in the formation of the free hydroxyl radical. On interaction between iron and Aβ, there is reduction of Fe³⁺ to Fe²⁺ and generation of H₂O₂, which further produces free hydroxyl radicals [63]. Accumulation of iron, ferritin and transferrin is seen in neuritic plaques in AD [64,65]. One study has shown that distribution pattern of iron in the brain of AD patients matches the distribution of senile plaques and NFTs [66]. Another study has shown that level of iron binding protein p97 is increased in blood serum and CSF in AD patients [67]. Author has suggested that level of p97 can be used as marker of the disease, can be useful in identifying the AD patients and also for assessing the effect of the therapeutic approaches.

The presence of transition metals in amyloid deposits in AD patients indicates direct interaction between these metals and Aβ [68-70]. Copper and zinc both can bind to the Aβ monomer via three histidine residues and one tyrosine residue, producing conformational change in the peptide which promotes its aggregation [71,72]. Copper is involved in free hydroxyl radical formation similar to iron. When copper interacts with the Aβ, cuproenzyme like complex is formed [71]. In this process, the electron is transferred from Aβ to Cu^2+, Cu²⁺ is converted to Cu⁺ forming Aβ radical [73]. During this process copper donates two electrons to the oxygen, generating H2O2 [73,74], and setting up conditions to further produce hydroxyl radical (Fenton type reaction) [75]. These data also suggest that ROS generated from the interaction between transition metals and Aβ are important contributors to the oxidative stress in Aβ-mediated neurotoxicity and AD pathogenesis. Another fact that suggest the possible role of copper in neurodegeneration is that copper is essential for the activity of many enzymes like, cytochrome-? oxidase and superoxide dismutase [76].

Aluminum has been suggested to be involved in AD pathology because of, high level of aluminum concentration in brains of AD patients, reports of aluminum toxicity and an association between aluminum concentration in water and the prevalence of AD [77]. Recently some studies have questioned the possible role of aluminum because aluminum content is not elevated in the brain regions of AD patients that are selectively vulnerable to the neuropathologic changes associated with the disease [78].

The linkage between aberrant metal homeostasis and AD pathology has made researchers think about AD treatment targeting Aβ-metal interaction and probably it can emerge as a promising therapeutic option. Some metal chelating compounds have been tested for their possible efficacy as a treatment option [79]. One such compound is clioquinol, which is Cu/Zn chelator and orally bioavailable, it blocks Aβ induced production H₂O₂ and Cu/Zn induced aggregation of Aβ peptide and can significantly reduce the Aβ deposition in the brains of transgenic mice [80,81]. One randomized, placebo controlled, double blind, clinical trial has been done using clioquinol in patients with moderately severe AD. Results showed that clioquinol treatment lowered plasma Aβ42 levels and slowed cognitive impairment in more severely affected patients during 36 week period [82].

Mitochondria Dysfunction and Oxidative Stress

Mitochondria are very essential organelles that are responsible for a variety of cellular functions like ATP synthesis, calcium homeostasis, cell survival and death. Mitochondrial electron transport chain is a major site for ROS production in the cell and mitochondria are highly vulnerable to oxidative stress [83,84]. Many studies have demonstrated the role of mitochondria dysfunction in AD pathogenesis. Hippocampal neurons have shown many mitochondrial and metabolic abnormalities in AD patients compared to age matched controls [85-87].

Studies have shown that oxidative phosphorylation is at lower level in AD, and this can be explained by both, energy deficits and the production of free radicals. Mitochondrial electron transport chain that results in the production of ATP by via reduction of oxygen to water is a complex enzymatic system which consists of 5 distinct phases [35]:

Complex 1 (NADH dehydrogenase)

Complex 2 (succinate dehydrogenase)

Complex 3 (ubiquinol-cytochrome-? oxidase)

Complex 4 (cytochrome-? oxidase)

Complex 5 (ATP synthase)

Research evidences have confirmed mitochondrial dysfunction in aging and neurodegenerative diseases such as AD, Huntington disease, and Parkinson disease, and particularly dysfunction in cytochrome-? oxidase in complex 4 in AD [88]. One study showed that postmortem cytochrome-? oxidase activity was around 25-30% lower than normal in cerebral cortex and platelets of AD patients [87]. Symonian and hyman have demonstrated lower than normal cytochrome-? oxidase activity in dentate gyrus and the CA4, CA3 and CA1 zones of hippocampus [89]. Another study has shown lower than normal levels of mRNA concentrations in subunit 1 and 3 of cytochrome-? oxidase [90]. In fact amounts of cytochrome-? oxidase are normal in brains of AD patients; it is the enzyme activity that is affected [91].

Studies have shown that Aβ may disrupt mitochondria function and contribute energy deficits and neuronal death seen in AD. The interaction between Aβ and mitochondria is also responsible for the free radicals production. Aβ was located in mitochondria in brains of AD patients, in transgenic mice and in neuroblastoma cells expressing human mutant APP [92,93]. In isolated mitochondria, Aβ can cause oxidative injury to the mitochondrial membrane, disrupt protein mobility and lipid polarity and inhibit the enzymes of mitochondria electron transport chain, leading to increased mitochondrial membrane permeability and cytochrome c release [94,95]. SODs are enzymes that provide protection against superoxide and other free radicals. The activity of one such enzyme manganese SOD (MnSOD) is decreased which further increases the levels of ROS and compromises the mitochondria function, and contributes to the loss of mitochondrial membrane potential and finally caspase activation and apoptosis [96].

Uncoupling proteins (UCPs) are mitochondrial anion carrier proteins which are a part of cellular protective mechanisms against oxidative damage to mitochondria. They are located on the inner mitochondrial membrane [97]. Upon activation by ROS and other products of lipid peroxidation, these proteins decrease the proton motive force, reduce the mitochondrial membrane potential and ATP production, eventually causing mitochondria uncoupling and decrease ROS production from mitochondria [98]. Therefore UCPs are considered as a protective mechanism against oxidative stress. In AD brains the expression of UCP2, 4 and 5 is significantly decreased and this protective mechanism becomes dysfunctional [99]. Evidences suggest that there is a relation between Aβ accumulation and expression and activation of UCPs. Upregulation of UCP2 and UCP4 protein levels in response to exposure to the superoxide is dysfunctional in SH-SY5Y neuroblastoma cells expressing APP mutant, mechanisms are unclear but it suggests that Aβ accumulation may lead to irreversible cellular modifications that render the cells vulnerable to the oxidative stress. Aβ accumulation is also linked to the loss of calcium homeostasis in cells by mitochondria [100].

Researchers have discovered mutations in cytochrome-? oxidase genes that segregate with late onset AD [101]. It has given considerable support to the link between mitochondrial function and cytochrome-? oxidase. Cytochrome-? oxidase is produced by effect of both mitochondrial and nuclear genes but mostly by two mitochondrial genes, CO1 and CO2 encoding for the subunit I and II respectively. CO3 is the gene encoding for the subunit III. One study has described DNA polymorphisms in CO1 and CO2 but not in CO3, that aggregate in AD [101]. However, further research concluded that these polymorphisms are not present in the mitochondrial genome but are rather nuclear pseudogenes [102,103].

Aβ Induced Toxicity and Oxidative Stress

Aβ is produced from the APP by proteolytic cleavage by two membrane bound proteases beta-secretase and gamma-secretase. Beta-secretase is also known as beta site APP cleaving enzyme 1 (BACE) and gamma-secretase is a multiprotein complex consisting of presenilin (PS), nicastrin (NCT), anterior pharynx defective 1 (APH1), and presenilin enhancer protein 2 (PEN-2) [1,104,105]. Beta-secretase and gamma-secretase cleaves APP at different sites and finally Aβ peptides of varying length are generated [1,104,106]. Among them, 42-amino acid form of Aβ is more toxic because of is faster self-aggregation into oligomers [1,106,107]. Research evidences suggest that soluble Aβ oligomers are the most neurotoxic and their level correlate with severity of cognitive decline in AD [106,107]. Alpha-secretase is a third protease that prevents the formation of toxic Aβ peptides. Dysfunctional activity of these three proteases, results in Aβ accumulation, which stimulates diverse cell signaling pathways, and lastly resulting in synaptic degeneration, neuronal loss, and cognitive decline [104,106-111].

Studies have implicated oxidative stress in Aβ induced neurotoxicity [112]. Levels of hydrogen peroxide and lipid peroxides could be increased with Aβ treatment within cell cultures in in vitro experiments [113]. Mutant forms of APP and PS-I can result in increased hydrogen peroxide and nitric oxide production as well as oxidative alterations of proteins and lipids, which were correlated with the age associated Aβ accumulation, this confirms that Aβ promotes oxidative stress [92,114-116]. Excessive activation of N-methyl D-aspartic acid (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors through NMDA agonists results in tremendous influx of Na+ and Ca++ and secondary influx of H2O, eventually causes acute cellular edema and narcotic cell death. The persistent elevation of Ca2+ causes disruption of the mitochondria, release of cytochrome C and activation of caspases, finally producing programmed cell death (apoptosis) [117]. In Hippocampal neuronal cell lines, the production of ROS by Aβ oligomers required the activation of NMDA receptors and subsequent increase in Ca++ influx. All these findings suggest possible role of soluble Aβ oligomers as a proximal neurotoxins and the involvement of oxidative stress in the synaptic impairment and neuronal loss induced by soluble Aβ oligomers [118]. Consistently, the natural antioxidants like, gingko biloba, curcumin, and green tea catechins have shown to exert neuroprotective functions by attenuating Aβ induced ROS generation and neuronal apoptosis [119-122].

Apart from mediating Aβ induced cytotoxicity, studies have shown that oxidative stress promotes the production of Aβ. Various studies in transgenic mice models overexpressing mutant APP, have shown that defects in antioxidant system caused elevated oxidative stress and significantly increased Aβ deposition, while dietary antioxidants lowered the elevated oxidized proteins and decreased Aβ levels and Aβ plaque burden in brain [123-125]. Based on these findings, overexpression of the MnSOD decreased oxidative stress and increased antioxidant defense capability in brains associated with reduction in Aβ plaque burden and restoration of some memory deficits [126]. Similarly, deletion of cytoplasmic Cu/Zn SOD was found to increase Aβ oligomerization suggesting the possible role of oxidative stress in Aβ oligomerization [127]. These all findings suggest that oxidative stress is important for Aβ oligomerization/deposition and plaque formation.

Many studies have focused on how oxidative stress increases Aβ production and revealed that oxidative stress decreases the activity of alpha-secretase while promoting the activities of beta-secretase and gamma-secretase, enzymes critical for generation of Aβ from APP [128-132]. Studies have demonstrated that oxidative stress activates major cell signaling c-Jun N-terminal kinase (JNK) pathway which causes induction of BACE and PS-1 expression and activation of gamma-secretase. As a result, more amount of Aβ is produced and its clearance is decreased leading to Aβ deposition, plaque formation and eventually neurotoxicity [133,134]. The activation of JNK pathway [135-137] and increased BACE and PS-1 activity [138-140] both have been detected in AD brains; thus, it is possible that elevated levels of oxidative stress in AD brains may initiate the activation of ROS sensitive cell signaling pathway including JNK, which induces the expression of BACE and PS1, ultimately enhancing the production of Aβ and the deterioration of cognitive function.

Studies have shown that neuronal oxidative damage was more in AD subjects with lesser amounts of Aβ deposition or in AD subjects with shorter disease duration [141,142]. In addition to this, there was an inverse relationship between the oxidative damage to nucleic acids and the amounts of intraneuronal Aβ42 in the hippocampus and subiculum of AD brains [143]. These strange observations have led to the hypothesis that Aβ may be playing a protective role against oxidative stress [144]. Evidences suggest that lower nanomolar levels of Aβ can be neurotrophic or neuroprotective [145,146]. Aβ, in normal physiological concentrations was shown to inhibit autooxidation of lipoproteins in CSF and plasma [147] and to increase hippocampal long term potentiation [148], whereas the higher nanomolar levels of Aβ caused the toxic effects. From all these findings, we can conclude that low levels of Aβ may have potential role in normal function of the cells, while the abnormal production, accumulation and aggregation of specific forms of Aβ, which can be increased by oxidative stress, may impair the neuronal activity and exacerbate neuronal oxidative insults, contributing to the pathological development of AD [146-149].

Hyperphosphorylated Tau

Hyperphosphorylated Tau is the major component of the NFTs, and is significantly correlated with neurodegeneration and cognitive decline in AD [104]. Surprisingly, neurons with NFTs showed significantly lower levels of 8-OHG despite obvious oxidative damage. This suggests that tau phosphorylation and NFT formation may have a protective role for neurons from oxidative stress [150]. However, research evidences suggest that tau is associated with oxidative stress in AD. In a Drosophila model of human tauopathy, reduction in gene dosage of thioredoxin reductase or mitochondrial SOD2 promotes tau induced neurodegenerative histopathological abnormalities and neuronal apoptosis [40]. While, treatment with the antioxidants like vitamin E and C decrease the level of ROS and tau induced neuronal death [39,151]. The link between tau pathology and oxidative stress has been demonstrated in transgenic mice models P301S and P301L. Studies have shown that reduced activity of NADH-ubiquinone oxidoreductase with mitochondrial dysfunction impairs mitochondrial oxidative phosphorylation and ATP synthesis [152-154]. Accordingly, Coenzyme Q10 (CoQ10) which is a key component of electron transport chain significantly reduces lipid peroxidation and increases complex 1 activity, consequently improves survival and behavioral deficits in P301S mice [155]. In addition to this, the convergence of Aβ and tau pathologies on mitochondria dysfunction was demonstrated in triple transgenic mouse model (PR5/APP/PS2) (tripleAD), which has both Aβ and tau histopathologic features of the disease in the brain of the mouse [156]. When Proteomics analysis of the tripleAD brain samples was done, it has demonstrated deregulation of 24 proteins, in which one third were mitochondrial proteins related to complex 1 and 4 of electron transport chain [157]. Interestingly, deregulation of mitochondrial complex 4 was shown to be Aβ dependent, while deregulation of complex I was tau dependent [157]. The effects of both Aβ and tau on mitochondrial function were found to be synergistic and age associated, which results in reduction of mitochondrial oxidative phosphorylation and ATP synthesis, eventually leading to the synaptic loss, and neuronal death [157].

Apolipoprotein E and Oxidative Stress

Apolipoprotein E (ApoE) gene is polymorphic and it has three isoforms: Apo ?2, Apo ?3 and Apo ?4. The ?4 allele has been linked to both late onset family forms and sporadic forms of AD, whereas ?2 allele was found to offer protection. In central nervous system, ApoE is produced mainly by astrocytes and take part in transport of cholesterol to neurons through ApoE receptors, and is a crucial cholesterol carrier in brain and has possible role in neuroplasticity-related phenomena because it requires changes in membrane lipids. One researcher has found that ApoE has beneficial effect for neuronal protection but it is isoforms dependent, like Apo ?4 isoform is less effective than Apo ?2 and Apo ?3 [158]. There is possibility that Apo ?4 may not be toxic but it simply has less protective effects than ?2 and ?3. Some researchers showed that ApoE has protective role against free radicals and has significant antioxidant property but it is also isoforms dependent like, effect is clearly perceptible with isoform ?2 but less so with ?3 and even less so with ?4 [159]. However, another study showed that ApoE is sensitive to free radical attack in isoform dependent manner. The isoform ?4 is more sensitive to free radical attack than isoform ?3 and ?3 is more sensitive than isoform ?2. An antioxidant like gingko biloba extract EGb 761, protects ApoE from oxidation in a similar isoform dependent manner, the Apo ?4 being maximally protected [160]. Further research has showed relation between lipid peroxidation in AD and ApoE genotype. They showed that the level of lipid peroxidation in AD is isoform dependent and were higher with Apo ?4 allele. The concentration of ApoE in brains of AD patients is inversely proportional to the level of lipid peroxidation, which confirms the hypothesis that ApoE has beneficial effect against lipid peroxidation and the effect is more pronounced with ?4 allele. Research finding showed that EGb 716 effectively decreases the level of lipid peroxidation in the brains of AD patients [161].

Inflammation

Inflammation also takes part in the production of free radicals. Deposition of Aβ initiates inflammatory cascade which attracts and activates microglia and astrocytes, leading to their aggregation around Aβ deposits, and release of pro-inflammatory mediators such as cytokines, chemokines, ROS, and complement proteins that may result in neuronal damage [162-164]. Microglia also has scavenger receptors by which it interacts with Aβ, causes ROS secretion and cell immobilization [165].

Antioxidant Therapeutics

The role of oxidative stress in AD pathology is very promising in development of future therapeutic strategies for prevention and possible treatment of AD. Various antioxidant therapies identified and studied on the basis of role of antioxidants in decreasing the ROS production and exerting neuroprotective effects on neurons in AD patients [166,167]. Most abundantly researched and studied are vitamins and carotene. Vitamin E (a-tocopherol), vitamin C (L-ascorbic acid), and β-carotene (Endogenous antioxidant compounds and also found in the diet) are chain breaking antioxidants which decrease free radical mediated damage in neuronal cells and help to inhibit dementia pathogenesis in mammalian cells. Vitamin B2 is an antioxidant and has been shown to increase choline acetyltransferase activity in cholinergic neurons cats and improves cognitive functions in AD patients [168].

Here, we are not mentioning each and every antioxidant therapeutic option because in last two decades there has been abundant research and studies for protective role of antioxidants in AD. We just mentioning the categories of the antioxidant therapies based on their target actions and the recent research in the same field. The possible categories are mentioned below:

Delanty and Dichter have made review of antioxidant therapies in neurological disorders and categorize various available antioxidants depending on whether compounds are endogenous or exogenous and their underlying mechanism of action [169].

•Endogenous enzymes, eg, superoxide dismutase, catalase, glutathione peroxidase

•Endogenous antioxidant compounds (also found in the diet), eg, a-tocopherol, ascorbic acid

•Other endogenous antioxidant substances, eg, uric acid, glutathione, melatonin

•Endogenous antioxidant cofactors, eg, selenium, coenzyme Q10

•Precursors and derivatives of endogenous antioxidant compounds and enzymes, eg, acetyl cysteine, polyethylene glycol superoxide dismutase

•Metal chelators, eg, deferoxamine

•Naturally occurring plant substances, eg, flavonoids (in gingko biloba and black tea), lycopene in (tomatoes), guilingji (a Chinese herbal medicine)

•Synthetic free radical compounds, eg, 21-aminosteroids, pyrrolopyrimidines, ebselen

•Compounds with other primary beneficial therapeutic effects, but that may also have free radical scavenging activity, eg, selegiline, probucol, carvedilol, aspirin, magnesium, statins [169]

Feng and Wang have described the various Antioxidant strategies for the AD [170]:

•Antioxidant therapies: vitamin E (a-tocopherol), vitamin C, β-carotene, vitamin B2

•Antioxidant Enzymes: superoxide dismutase (MnSOD-Mitochondrial, Cu/Zn SOD-cytoplasmic), catalase, glutathione peroxidase

•Mitochondrial targeted Antioxidants: vitamin A, carotenoids, vitamin C, and vitamin E and others (a-lipoic acid (LA), coenzymeQ10, NADH, Mito Q, Szeto Schiller (SS) peptide, and glutathione)

•Dietary supplements: omega-3 polyunsaturated fatty acid (docosahexaenoic acid), caffeine, and curry spice curcumin

•Traditional Herbal Antioxidants: three major alkaloids in CoptidisRhizoma-groenlandicine, berberine, and palmatine, silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybummarianum), Ginkgo biloba, ginsenosides isolated from Panax spp. ginseng herb [171]

•Other Antioxidants: Melatonin, Monoamine Oxidase-B Inhibitor (Selegiline), and Oestrogen

Melatonin is endogenous hormone synthesized in pineal gland. It stimulates the expression and activity of glutathione peroxidase, SOD, and NO synthetase, by this it scavenges ROS and RNS generated in mitochondria, eventually contributes to the reduction of oxidative damage in cells [172,173]. Selegiline is a selective monoamine oxidase-B inhibitor with possible antioxidant properties [174]. One study reported that in patients with moderate to severe AD, treatment with selegiline reduces neuronal damage and slows the progression of AD [175]. Estrogen has been shown to have role in neuronal protection against oxidative damage and neuroprotective effects [176], but it does not produce any beneficial effects on cognition and functioning in AD [170,177].

Tritrpenoids, are polycyclic compound derived from the linear hydrocarbon squalene. They are widely distributed in edible and medicinal plants [178]. Xanthoceraside, a triterpene derived from the husk of xanthocerassorbifolia Bunge, is used by Chinese as a traditional remedy for rheumatism. One researcher has reported that xanthoceraside ameliorates the oxidative stress and inflammatory responses induced by Aβ25-35, attenuates memory impairments and is a potential candidate for an AD treatment [179]. Another triterpenoid, 2-Cyano-3, 12-Dioxooleana-1, 9-Dien-28-Oic acid-Methylamide (CDDO-MA) is studied in Tg19959 mice, after 3 months of administration, it significantly improved spatial memory retention, reduced plaque burden, Aβ42 levels, microgliosis and oxidative stress in Tg19959 mice [180].

The Rhinacanthusnasutus is an herb found in Thailand and South East Asia, belongs to Acanthaceae family [181]. Extracts from the leaf and root contain varying amounts of phenolic and flavonoid compounds, triterpenoid-lupeol, and the sterols stigmasterols and β-sitosterol. The ethanol extracts of leaf and root have high free radical scavenging effects. It protects HT-22 cells (mouse hippocampal cell lines) against glutamate and Aβ toxicity. This protection is combination of effects of various compounds, resulting from more than one mechanism, including free radical scavenging, inhibition of caspase and growth factor production [182].Puerarin, a major isoflavone glycoside from Kudzu root (Puerarialobata) has been reported to exhibit estrogen like and antioxidant properties. Pretreatment of primary hippocampal neurons with peurarin significantly reduced Aβ25-35-induced oxidative stress possibly through scavenging of ROS, inhibiting lipid peroxidation and interrupting the glycogen synthase kinase-3β (GSK-3β) signaling [183].

Many antioxidants have been identified and studied for the possible therapeutic role in AD, but none has given consistent beneficial results, therefore their efficacy in prevention and possible treatment of AD is always a question. Recently, many dietary and herbal antioxidants and other antioxidants targeting the mitochondria have shown promising results but it requires further research and confirmation of the efficacy.

Conclusion

Growing evidence suggests that oxidative stress plays a major role in the pathogenesis of AD. This production of the free radicals has been linked to the disruption of the metal ion homeostasis, mitochondrial dysfunction, genetic mutations, increased Aβ42 production and aggregation, decreased clearance of Aβ, inflammatory mediators, and tau hyperphosphorylation, in a manner of vicious pathophysiological cycle. Combination of all these processes results into oxidation of lipids, proteins and nucleic acids, and their products have been considered as blood biomarkers for early diagnosis of AD, but their efficacy as early biomarkers is still a question. Regardless a primary or secondary event, oxidative stress is important factor contributing to the pathogenesis of AD. Free radical scavenging or prevention of their formation may delay the onset or slow down the progression of AD through various mechanisms, including reduction of oxidative stress mediated neurotoxicity, inhibition of Aβ production and aggregation, restoration of mitochondria function and metal homeostasis, reduction in tau phosphorylation and polymerization. Accordingly, research evidences suggest that various antioxidant therapies play role in free radical scavenging and reduce oxidative stress, therefore they are possible therapeutic options and research targets. Some studies also have shown that metal chelators have some role in reduction in oxidative stress arising due to metal dyshomeostasis, but further research is required for confirmation of their therapeutic role.

References

1. Querfurth HW, LaFerla FM (2010) Alzheimer's disease. N Engl J Med 362: 329-344.
2. Alzheimer's Association (2010) Alzheimer's disease facts and figures. Alzheimers Dement 6: 158-194.
3. Dong MJ, Peng B, Lin XT, Zhao J, Zhou YR, et al. (2007) The prevalence of dementia in the People's Republic of China: a systematic analysis of 1980-2004 studies. Age Ageing 36: 619-624.
4. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, et al. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366: 2112-2117.
5. Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, et al. (2008) Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol 7: 812-826.
6. Martins RN, Clarnette R, Fisher C, Broe GA, Brooks WS, et al. (1995) ApoE genotypes in Australia: roles in early and late onset Alzheimer's disease and Down's syndrome. Neuroreport 6: 1513-1516.
7. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, et al. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360: 672-674.
8. Scheuner D, Eckman C, Jensen M, Song X, Citron M, et al. (1996) Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 2: 864-870.
9. Rebeck GW, Reiter JS, Strickland DK, Hyman BT (1993) Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron 11: 575-580.
10. Myllykangas L, Polvikoski T, Sulkava R, Verkkoniemi A, Crook R, et al. (1999) Genetic association of alpha2-macroglobulin with Alzheimer's disease in a Finnish elderly population. Ann Neurol 46: 382-390.
11. Tanzi RE, Kovacs DM, Kim TW, Moir RD, Guenette SY, et al. (1996) The gene defects responsible for familial Alzheimer's disease. Neurobiol Dis 3: 159-168.
12. Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, et al. (1997) Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature 389: 603-606.
13. Agostinho P, Cunha RA, Oliveira C (2010) Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease. Curr Pharm Des 16: 2766-2778.
14. Harman D (1995) Free radical theory of aging: Alzheimer’s disease pathogenesis. Age (Omaha). 18, 97–119.
15. Sayre LM, Smith MA, Perry G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8: 721-738.
16. Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G (2000) Oxidative stress in Alzheimer's disease. BiochimBiophysActa 1502: 139-144.
17. Sokoloff L (1999) Energetics of functional activation in neural tissues. Neurochem Res 24: 321-329.
18. Tholey G, Ledig M (1990) Neuronal and astrocytic plasticity: metabolic aspects. Ann Med Interne (Paris) 141 Suppl 1: 13-18.
19. Christen Y (2000) Oxidative stress and Alzheimer disease. Am J ClinNutr 71: 621S-629S.
20. Hazel JR, Williams EE (1990) The role of alterations in membrane lipid composition in enabling physiological adaptation of organisms to their physical environment. Prog Lipid Res 29: 167-227.
21. Benzi G, Moretti A (1995) Are reactive oxygen species involved in Alzheimer's disease? Neurobiol Aging 16: 661-674.
22. Calabrese V, Scapagnini G, Stella AMG, Bates TE, Clark JB (2001) Mitochondrial Involvement in Brain Function and Dysfunction: Relevance to Aging, Neurodegenerative Disorders and Longevity. Neurochem. Res. 26, 739–764.
23. Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, et al. (1994) Advanced Maillard reaction end products are associated with Alzheimer disease pathology. ProcNatlAcadSci U S A 91: 5710-5714.
24. Ledesma MD, Bonay P, Colaço C, Avila J (1994) Analysis of microtubule-associated protein tau glycation in paired helical filaments. J BiolChem 269: 21614-21619.
25. Vitek MP, Bhattacharya K, Glendening JM, Stopa E, Vlassara H, et al. (1994) Advanced glycation end products contribute to amyloidosis in Alzheimer disease. ProcNatlAcadSci U S A 91: 4766-4770.
26. Yan SD, Chen X, Schmidt AM, Brett J, Godman G, et al. (1994) Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. ProcNatlAcadSci U S A 91: 7787-7791.
27. Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence of neuronal oxidative damage in Alzheimer's disease. Am J Pathol 149: 21-28.
28. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer's disease. J Neurosci 17: 2653-2657.
29. Montine TJ, Amarnath V, Martin ME, Strittmatter WJ, Graham DG (1996) E-4-hydroxy-2-nonenal is cytotoxic and cross-links cytoskeletal proteins in P9 neuroglial cultures. Am J Pathol 148: 89-93.
30. Sayre LM, Zelasko DA, Harris PL, Perry G, Salomon RG, et al. (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer's disease. J Neurochem 68: 2092-2097.
31. Smith MA, Rudnicka-Nawrot M, Richey PL, Praprotnik D, Mulvihill P, et al. (1995) Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease. J Neurochem 64: 2660-2666.
32. Smith MA, Perry G, Richey PL, Sayre LM, Anderson VE, et al. (1996) Oxidative damage in Alzheimer's. Nature 382: 120-121.
33. Zhao Y, Zhao B (2013) Oxidative stress and the pathogenesis of Alzheimer's disease. Oxid Med Cell Longev 2013: 316523.
34. Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, et al. (2012) Mitochondria, oxidative stress and neurodegeneration. J NeurolSci 322: 254-262.
35. Chen Z, Zhong C (2014) Oxidative stress in Alzheimer's disease. Neurosci Bull 30: 271-281.
36. Yan MH, Wang X, Zhu X (2013) Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free RadicBiol Med 62: 90-101.
37. Ayton S, Lei P, Bush AI (2013) Metallostasis in Alzheimer's disease. Free RadicBiol Med 62: 76-89.
38. Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer's disease. NeurochemInt 62: 540-555.
39. Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117: 236-245.
40. Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156: 1051-1063.
41. Candore G, Bulati M, Caruso C, Castiglia L, Colonna-Romano G, et al. (2010) Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications. Rejuvenation Res. 13, 301–313.
42. Lee YJ, Han SB, Nam SY, Oh KW, Hong JT (2010) Inflammation and Alzheimer's disease. Arch Pharm Res 33: 1539-1556.
43. Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, et al. (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. ExpNeurol 150: 40-44.
44. Omar RA, Chyan YJ, Andorn AC, Poeggeler B, Robakis NK, et al. (1999) Increased Expression but Reduced Activity of Antioxidant Enzymes in Alzheimer's Disease. J Alzheimers Dis 1: 139-145.
45. Ansari MA, Scheff SW (2010) Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J NeuropatholExpNeurol 69: 155-167.
46. Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, et al. (2010) Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons. J Alzheimers Dis 20 Suppl 2: S609-631.
47. Mattson MP (2004) Pathways towards and away from Alzheimer's disease. Nature 430: 631-639.
48. Reddy PH (2006) Mitochondrial oxidative damage in aging and Alzheimer's disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol 2006: 31372.
49. Skoumalová A, Hort J (2012) Blood markers of oxidative stress in Alzheimer's disease. J Cell Mol Med 16: 2291-2300.
50. Söderberg M, Edlund C, Kristensson K, Dallner G (1991) Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease. Lipids 26: 421-425.
51. Lovell MA, Ehmann WD, Butler SM, Markesbery WR (1995) Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer's disease. Neurology 45: 1594-1601.
52. Butterfield DA, Reed T, Perluigi M, De Marco C, Coccia R, et al. (2006) Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment. NeurosciLett 397: 170-173.
53. Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, et al. (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64: 1152-1156.
54. Praticò D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, et al. (2000) Increased 8,12-iso-iPF2alpha-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 48: 809-812.
55. Roberts LJ 2nd1, Montine TJ, Markesbery WR, Tapper AR, Hardy P, et al. (1998) Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J BiolChem 273: 13605-13612.
56. Montine TJ, Markesbery WR, Morrow JD, Roberts LJ 2nd (1998) Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer's disease. Ann Neurol 44: 410-413.
57. Singh M, Dang TN, Arseneault M, Ramassamy C (2010) Role of by-products of lipid oxidation in Alzheimer's disease brain: a focus on acrolein. J Alzheimers Dis 21: 741-756.
58. Ahmed N, Ahmed U, Thornalley PJ, Hager K, Fleischer G, et al. (2005) Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment. J Neurochem 92: 255-263.
59. Butterfield DA, Reed TT, Perluigi M, De Marco C, Coccia R, et al. (2007) Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease. Brain Res 1148: 243-248.
60. Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol 36: 747-751.
61. Mullaart E, Boerrigter ME, Ravid R, Swaab DF, Vijg J (1990) Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients. Neurobiol Aging 11: 169-173.
62. Deibel MA, Ehmann WD, Markesbery WR (1996) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. J NeurolSci 143: 137-142.
63. Honda K, Casadesus G, Petersen RB, Perry G, Smith MA (2004) Oxidative stress and redox-active iron in Alzheimer's disease. Ann N Y AcadSci 1012: 179-182.
64. Loeffler DA, Connor JR, Juneau PL, Snyder BS, Kanaley L, et al. (1995) Transferrin and iron in normal, Alzheimer's disease, and Parkinson's disease brain regions. J Neurochem 65: 710-724.
65. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer's disease. Free RadicBiol Med 23: 134-147.
66. Smith MA, Harris PL, Sayre LM, Perry G (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. ProcNatlAcadSci U S A 94: 9866-9868.
67. Kennard ML, Feldman H, Yamada T, Jefferies WA (1996) Serum levels of the iron binding protein p97 are elevated in Alzheimer's disease. Nat Med 2: 1230-1235.
68. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. J NeurolSci 158: 47-52.
69. Lee JY, Mook-Jung I, Koh JY (1999) Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid precursor protein transgenic mice. J Neurosci 19: RC0.
70. Zhang J, Liu Q, Chen Q, Liu NQ, Li FL, et al. (2006) Nicotine attenuates beta-amyloid-induced neurotoxicity by regulating metal homeostasis. FASEB J 20: 1212-1214.
71. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, et al. (2001) Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J. Biol. Chem. 276, 20466–20473.
72. Hesse L, Beher D, Masters CL, Multhaup G (1994) The beta A4 amyloid precursor protein binding to copper. FEBS Lett 349: 109-116.
73. Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, et al. (2002) Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J BiolChem 277: 40302-40308.
74. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, et al. (1999) Cu(II) potentiation of alzheimerabeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J BiolChem 274: 37111-37116.
75. Lynch T, Cherny RA, Bush AI (2000) Oxidative processes in Alzheimer's disease: the role of abeta-metal interactions. ExpGerontol 35: 445-451.
76. Linder MC, Hazegh-Azam M (1996) Copper biochemistry and molecular biology. Am J ClinNutr 63: 797S-811S.
77. Crapper DR, Quittkat S, Krishnan SS, Dalton AJ, De Boni U (1980) Intranuclearaluminum content in Alzheimer's disease, dialysis encephalopathy, and experimental aluminum encephalopathy. ActaNeuropathol 50: 19-24.
78. Bjertness E, Candy JM, Torvik A, Ince P, McArthur F, et al. (1996) Content of brain aluminum is not elevated in Alzheimer disease. Alzheimer Dis AssocDisord 10: 171-174.
79. Bolognin S, Messori L, Zatta P (2009) Metal ion physiopathology in neurodegenerative disorders. Neuromolecular Med 11: 223-238.
80. Bush AI (2002) Metal complexing agents as therapies for Alzheimer's disease. Neurobiol Aging 23: 1031-1038.
81. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, et al. (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30: 665-676.
82. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, et al. (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch. Neurol. 60, 1685–1691.
83. Tan S, Sagara Y, Liu Y, Maher P, Schubert D (1998) The regulation of reactive oxygen species production during programmed cell death. J Cell Biol 141: 1423-1432.
84. Grivennikova VG, Vinogradov AD (2006) Generation of superoxide by the mitochondrial Complex I. BiochimBiophysActa 1757: 553-561.
85. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, et al. (2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 21: 3017-3023.
86. Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, et al. (2006) Mitochondrial abnormalities and oxidative imbalance in Alzheimer disease. J Alzheimers Dis 9: 147-153.
87. Mutisya EM, Bowling AC, Beal MF (1994) Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem 63: 2179-2184.
88. Beal MF (1995) Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 38: 357-366.
89. Simonian NA, Hyman BT (1993) Functional alterations in Alzheimer's disease: diminution of cytochrome oxidase in the hippocampal formation. J NeuropatholExpNeurol 52: 580-585.
90. Chandrasekaran K, Giordano T, Brady DR, Stoll J, Martin LJ, et al. (1994) Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease. Brain Res Mol Brain Res 24: 336-340.
91. Parker WD Jr1, Parks JK (1995) Cytochrome c oxidase in Alzheimer's disease brain: purification and characterization. Neurology 45: 482-486.
92. Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, et al. (2006) Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 15: 1437-1449.
93. Caspersen C, Wang N, Yao J, Sosunov A, Chen X, et al. (2005) Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J 19: 2040-2041.
94. Rodrigues CM, Solá S, Brito MA, Brondino CD, Brites D, et al. (2001) Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. BiochemBiophys Res Commun 281: 468-474.
95. Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 80: 91-100.
96. Anantharaman M, Tangpong J, Keller JN, Murphy MP, Markesbery WR, et al. (2006) Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer's disease. Am J Pathol 168: 1608-1618.
97. Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, et al. (2004) The biology of mitochondrial uncoupling proteins. Diabetes 53 Suppl 1: S30-135.
98. Echtay KS (2007) Mitochondrial uncoupling proteins--what is their physiological role? Free RadicBiol Med 43: 1351-1371.
99. de la Monte SM, Wands JR (2006) Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis 9: 167-181.
100. Wu Z, Zhang J, Zhao B (2009) Superoxide anion regulates the mitochondrial free Ca2+ through uncoupling proteins. Antioxid Redox Signal 11: 1805-1818.
101. Davis RE, Miller S, Herrnstadt C, Ghosh SS, Fahy E, et al. (1997) Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease. ProcNatlAcadSci U S A 94: 4526-4531.
102. Hirano M, Shtilbans A, Mayeux R, Davidson MM, DiMauro S, et al. (1997) Apparent mtDNAheteroplasmy in Alzheimer's disease patients and in normals due to PCR amplification of nucleus-embedded mtDNApseudogenes. ProcNatlAcadSci U S A 94: 14894-14899.
103. Wallace DC, Stugard C, Murdock D, Schurr T, Brown MD (1997) Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations. ProcNatlAcadSci U S A 94: 14900-14905.
104. Goedert M, Spillantini MG (2006) A century of Alzheimer's disease. Science 314: 777-781.
105. Steiner H (2004) Uncovering gamma-secretase. Curr Alzheimer Res 1: 175-181.
106. Walsh DM, Selkoe DJ (2007) A beta oligomers - a decade of discovery. J Neurochem 101: 1172-1184.
107. Yankner BA, Lu T (2009) Amyloid beta-protein toxicity and the pathogenesis of Alzheimer disease. J BiolChem 284: 4755-4759.
108. Esler WP, Wolfe MS (2001) A portrait of Alzheimer secretases--new features and familiar faces. Science 293: 1449-1454.
109. Roberson ED, Mucke L (2006) 100 years and counting: prospects for defeating Alzheimer's disease. Science 314: 781-784.
110. Maccioni RB, Muñoz JP, Barbeito L (2001) The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch Med Res 32: 367-381.
111. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, et al. (1996) Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.
112. Butterfield DA (2002) Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer's disease brain. A review. Free Radic Res 36: 1307-1313.
113. Mohmmad Abdul H, Sultana R, Keller JN, St Clair DK, Markesbery WR, et al. (2006) Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1-42), HO and kainic acid: implications for Alzheimers disease. J. Neurochem. 96, 1322–1335.
114. Matsuoka Y, Picciano M, La Francois J, Duff K (2001) Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease. Neuroscience 104: 609-613.
115. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, et al. (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70: 2212-2215.
116. Apelt J, Bigl M, Wunderlich P, Schliebs R (2004) Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int. J. Dev. Neurosci. 22, 475–484.
117. Matute C, Alberdi E, Domercq M, Sánchez-Gómez MV, Pérez-Samartín A, et al. (2007) Excitotoxic damage to white matter. J Anat 210: 693-702.
118. De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, et al. (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 282, 11590–11601.
119. Cole GM, Teter B, Frautschy SA (2007) Neuroprotective effects of curcumin. AdvExp Med Biol 595: 197-212.
120. Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MB (2008) Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr 138: 1578S-1583S.
121. Zhao Y, Zhao B (2012) Natural antioxidants in prevention and management of Alzheimer's disease. Front Biosci (Elite Ed) 4: 794-808.
122. Smith JV, Luo Y (2004) Studies on molecular mechanisms of Ginkgo biloba extract. ApplMicrobiolBiotechnol 64: 465-472.
123. Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, et al. (2004) Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 89: 1308-1312.
124. Nishida Y, Yokota T, Takahashi T, Uchihara T, Jishage K, et al. (2006) Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse. BiochemBiophys Res Commun 350: 530-536.
125. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, et al. (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21: 8370-8377.
126. Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, et al. (2009) Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer’s disease. FASEB J. 23, 2459–2466.
127. Murakami K, Murata N, Noda Y, Tahara S, Kaneko T, et al. (2011) SOD (copper/zinc superoxide dismutase) deficiency drives amyloid �² protein oligomerization and memory loss in mouse model of Alzheimer disease. J BiolChem 286: 44557-44568.
128. Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, et al. (2002) Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10: 279-288.
129. Oda A, Tamaoka A, Araki W (2010) Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells. J Neurosci Res 88: 1137-1145.
130. Yoo MH, Gu X, Xu XM, Kim JY, Carlson BA, et al. (2010) Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease. Antioxid Redox Signal 12: 819-827.
131. Chen L, Na R, Gu M, Richardson A, Ran Q (2008) Lipid peroxidation up-regulates BACE expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J Neurochem 107: 197-207.
132. 132. Quiroz-Baez R, Rojas E, Arias C (2009) Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gamma-secretase expression. Neurochem. Int. 55, 662–670.
133. Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, et al. (2008) Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J. Neurochem. 104, 683–695.
134. Shen C, Chen Y, Liu H, Zhang K, Zhang T, et al. (2008) Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J BiolChem 283: 17721-17730.
135. Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, et al. (2001) Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem 76: 435-441.
136. Zhu X, Ogawa O, Wang Y, Perry G, Smith MA (2003) JKK, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease. J Neurochem 85: 87-93.
137. Lagalwar S, Guillozet-Bongaarts AL, Berry RW, Binder LI (2006) Formation of phospho-SAPK/JNK granules in the hippocampus is an early event in Alzheimer disease. J NeuropatholExpNeurol 65: 455-464.
138. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59: 1381-1389.
139. Yang LB, Lindholm K, Yan R, Citron M, Xia W, et al. (2003) Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9: 3-4.
140. Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, et al. (2007) Expression of APP pathway mRNAs and proteins in Alzheimer's disease. Brain Res 1161: 116-123.
141. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, et al. (2001) Oxidative damage is the earliest event in Alzheimer disease. J NeuropatholExpNeurol 60: 759-767.
142. Nunomura A, Chiba S, Lippa CF, Cras P, Kalaria RN, et al. (2004) Neuronal RNA oxidation is a prominent feature of familial Alzheimer's disease. Neurobiol Dis 17: 108-113.
143. Nunomura A, Tamaoki T, Tanaka K, Motohashi N, Nakamura M, et al. (2010) Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease. Neurobiol Dis 37: 731-737.
144. Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, et al. (2006) Involvement of oxidative stress in Alzheimer disease. J NeuropatholExpNeurol 65: 631-641.
145. Luo Y, Sunderland T, Roth GS, Wolozin B (1996) Physiological levels of beta-amyloid peptide promote PC2 cell proliferation. NeurosciLett 217: 125-128.
146. Plant LD, Boyle JP, Smith IF, Peers C, Pearson HA (2003) The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci 23: 5531-5535.
147. Kontush A, Berndt C, Weber W, Akopyan V, Arlt S, et al. (2001) Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free RadicBiol Med 30: 119-128.
148. Puzzo D, Privitera L, Leznik E, Fà M, Staniszewski A, et al. (2008) Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 28: 14537-14545.
149. Zou K, Gong JS, Yanagisawa K, Michikawa M (2002) A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J Neurosci 22: 4833-4841.
150. Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, et al. (2007) Signal transduction cascades associated with oxidative stress in Alzheimer's disease. J Alzheimers Dis 11: 143-152.
151. Cente M, Filipcik P, Pevalova M, Novak M (2006) Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci 24: 1085-1090.
152. David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, et al. (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J BiolChem 280: 23802-23814.
153. Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, et al. (2011) Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J 25: 4063-4072.
154. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, et al. (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53: 337-351.
155. Elipenahli C, Stack C, Jainuddin S, Gerges M, Yang L, et al. (2012) Behavioral improvement after chronic administration of coenzyme Q0 in P301S transgenic mice. J Alzheimers Dis 28: 173-182.
156. Eckert A, Schulz KL, Rhein V, Götz J (2010) Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. MolNeurobiol 41: 107-114.
157. Rhein V, Song X, Wiesner A, Ittner LM, Baysang G, et al. (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. ProcNatlAcadSci U S A 106: 20057-20062.
158. Poirier J (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci 17: 525-530.
159. Miyata M, Smith JD (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet 14: 55-61.
160. Jolivalt C, Leininger-Muller B, Bertrand P, Herber R, Christen Y, et al. (2000) Differential oxidation of apolipoprotein E isoforms and interaction with phospholipids. Free RadicBiol Med 28: 129-140.
161. Ramassamy C, Averill D, Beffert U, Bastianetto S, Theroux L, et al. (1999) Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype. Free RadicBiol Med 27: 544-553.
162. Tuppo EE, Arias HR (2005) The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 37: 289-305.
163. Johnstone M, Gearing AJ, Miller KM (1999) A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 93: 182-193.
164. Smits HA, Rijsmus A, van Loon JH, Wat JW, Verhoef J, et al. (2002) Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J Neuroimmunol 127: 160-168.
165. El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, et al. (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382: 716-719.
166. Mecocci P, Tinarelli C, Schulz RJ, Polidori MC (2014) Nutraceuticals in cognitive impairment and Alzheimer's disease. Front Pharmacol 5: 147.
167. Foy CJ, Passmore AP, Vahidassr MD, Young IS, Lawson JT (1999) Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease. QJM 92: 39-45.
168. Nadeau A, Roberge AG (1988) Effects of vitamin B2 supplementation on choline acetyltransferase activity in cat brain. Int J VitamNutr Res 58: 402-406.
169. Delanty N, Dichter MA (2000) Antioxidant therapy in neurologic disease. Arch Neurol 57: 1265-1270.
170. Feng Y, Wang X (2012) Antioxidant therapies for Alzheimer's disease. Oxid Med Cell Longev 2012: 472932.
171. Kim YC, Kim SR, Markelonis GJ, Oh TH (1998) Ginsenosides Rb1 and Rg3 protect cultured rat cortical cells from glutamate-induced neurodegeneration. J Neurosci Res 53: 426-432.
172. Nishida S (2005) Metabolic effects of melatonin on oxidative stress and diabetes mellitus. Endocrine 27: 131-136.
173. Fusco D, Colloca G, Lo Monaco MR, Cesari M (2007) Effects of antioxidant supplementation on the aging process. ClinInterv Aging 2: 377-387.
174. Thomas T (2000) Monoamine oxidase-B inhibitors in the treatment of Alzheimer's disease. Neurobiol Aging 21: 343-348.
175. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, et al. (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336: 1216-1222.
176. Goodman Y, Bruce AJ, Cheng B, Mattson MP (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem 66: 1836-1844.
177. Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, et al. (2000) Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA 283: 1007-1015.
178. Szakiel A, PÄ…czkowski C, Pensec F, Bertsch C (2012) Fruit cuticular waxes as a source of biologically active triterpenoids. Phytochem Rev 11: 263-284.
179. Lu P, Mamiya T, Lu L, Mouri A, Ikejima T, et al. (2012)Xanthoceraside attenuates amyloid I2 peptideââ��-induced learning and memory impairments in mice. Psychopharmacology (Berl) 219: 181-190.
180. Dumont M, Wille E, Calingasan NY, Tampellini D, Williams C, et al. (2009) Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer's disease. J Neurochem 109: 502-512.
181. Brimson JM, Tencomnao T (2011) Rhinacanthusnasutus protects cultured neuronal cells against hypoxia induced cell death. Molecules 16: 6322-6338.
182. Brimson JM, Brimson SJ, Brimson CA, Rakkhitawatthana V, Tencomnao T (2012) Rhinacanthusnasutus Extracts Prevent Glutamate and Amyloid-β Neurotoxicity in HT-22 Mouse Hippocampal Cells: Possible Active Compounds Include Lupeol, Stigmasterol and β-Sitosterol. Int. J. Mol. Sci. 13, 5074–5097.
183. Zou Y, Hong B, Fan L, Zhou L, Liu Y, et al. (2013) Protective effect of puerarin against beta-amyloid-induced oxidative stress in neuronal cultures from rat hippocampus: involvement of the GSK-3�²/Nrf2 signaling pathway. Free Radic Res 47: 55-63.