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Abstract
Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2013, Article ID 316523, 10 pages http://dx.doi.org/10.1155/2013/316523 Review Article 1 2 Yan Zhao and Baolu Zhao Department of Bioengineering, Harbin Institute of Technology at Weihai, Weihai, Shandong 264209, China State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China Correspondence should be addressed to Yan Zhao; [email protected] and Baolu Zhao; [email protected] Received 25 May 2013; Accepted 3 July 2013 Academic Editor: Claudio ´ M. Gomes Copyright © 2013 Y. Zhao and B. Zhao. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. Patients with AD suffer a gradual deterioration of memory and other cognitive functions, which eventually leads to a complete incapacity and death. A complicated array of molecular events has been implicated in the pathogenesis of AD. eTh major pathological characteristics of AD brains are the presence of senile plaques, neurob fi rillary tangles, and neuronal loss. Growing evidence has demonstrated that oxidative stress is an important factor contributing to the initiation and progression of AD. However, the mechanisms that lead to the disruption of redox balance and the sources of free radicals remain elusive. eTh excessive reactive oxygen species may be generated from mechanisms such as mitochondria dysfunction and/or aberrant accumulation of transition metals, while the abnormal accumulation of Abeta and tau proteins appears to promote the redox imbalance. The resulted oxidative stress has been implicated in Abeta- or tau-induced neurotoxicity. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Abeta and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD. 1. Introduction filaments (PHFs) structures, which contain mainly self- aggregated hyperphosphorylated tau, a multifunctional pro- Alzheimer’s disease (AD) is the most common neurodegen- tein involved in microtubule assembly and stabilization [6]. erative disease that causes dementia in the elderly. It is char- Accumulating evidence has shown that the presence of exten- acterized by the gradual deterioration of memory and other sive oxidative stress is a characteristic of AD brains in addi- cognitive functions, which eventually leads to a complete tion to theestablished pathologyofsenileplaques andNFT incapacity and death of the patients within 3 to 9 years aeft r [7]. It has been demonstrated that the levels of protein car- diagnosis [1]. Increasing age is a major risk factor for sporadic bonyls and 3-nitrotyrosine, which are resulted from protein forms of AD. As the elderly population of the world continues oxidation, and markers of oxidative damage to DNA and to increase, the prevalence of AD has increased remarkably RNA, such as 8-hydroxydeoxyguanosine (8-OHdG) and 8- worldwide, andADhas become oneofthe leadingcauses hydroxyguanosine, are elevated in AD brains [8–12]. Prod- of disability and death among the elderly [2–5]. Despite the ucts of lipid peroxidation, such as malondialdehyde (MDA), tremendous progress that has been made in AD research in 4-hydroxynonenal, and F -isoprostanes, are also increased the past few decades, the exact cause and pathogenesis of in multiple brain regions and cerebrospinal u fl id (CSF) of AD are not completely understood, and currently, there is no patients with AD or mild cognitive impairment (MCI) [13– eecti ff ve treatment for the disease. 17]. In addition to theaccumulationoffreeradical damage, eTh major pathological characteristics of AD brains are alterations in the activities or expression of antioxidant en- the presence of senile plaques, neurofibrillary tangles (NFTs), zymes such as superoxide dismutase (SOD) and catalase have and neuronal loss [1, 6]. Senile plaques are mainly composed been observed in both central nervous system and periph- of beta-amyloid peptide (Abeta) that is produced from eral tissues of AD patients [17–20]. Moreover, in AD and proteolytic cleavage of the transmembrane amyloid precursor MCI brains, the increased oxidative damage to lipids and protein (APP). NFTs are formed by arrays of paired helical proteins andthe declineofglutathione andantioxidant 2 Oxidative Medicine and Cellular Longevity enzyme activities are more localized to the synapses and cor- soluble Abeta oligomers required the activation of N-methyl- relate with the severity of the disease, suggesting an involve- D-aspartate (NMDA) receptor and was associated with a ment of oxidative stress in AD-related synaptic loss [21]. rapidincreaseinneuronalcalcium levels,suggestingapos- Importantly, many of the previously mentioned studies show sible role of soluble Abeta oligomers as proximal neurotoxins elevations of oxidative stress in MCI, which is proposed as and the involvement of oxidative stress in the synaptic impair- an intermediate state between normal aging and dementia, ment and neuronal loss induced by soluble Abeta oligomers indicating that the oxidative stress damage in AD may occur [36]. Consistently, it has been demonstrated in AD cell and preceding the onset of the disease. eTh se results suggest that animal models that natural antioxidants, such as EGb 761, oxidative stress may be one of the earliest alterations that curcumin, and green tea catechins, can exert neuroprotective occur during the initiation and development of AD. functions by attenuating Abeta-induced ROS generation and While oxidative stress has emerged as one of the impor- neuronal apoptosis [37–40]. tant factors in AD pathogenesis, the mechanisms by which In addition to mediating Abeta-induced cytotoxity, theredox balanceisaltered andthe sourcesoffreeradicals numerous studies have suggested that oxidative stress pro- remain elusive. The present paper reviews the involvement motes the production of Abeta. It was demonstrated that of abnormal accumulation of Abeta and tau proteins in the defects in antioxidant defense system caused elevated oxida- induction of redox imbalance and the generation of free rad- tive stress and significantly increased Abeta deposition in icals through mechanisms such as mitochondria dysfunction transgenic mice overexpressing APP mutant [41, 42], while and/or transition metal homeostasis imbalance and discusses dietary antioxidants such as curcumin lowered the elevation the mechanisms by which oxidative stress promotes Abeta- of oxidized proteins and decreased brain Abeta levels and and tau-mediated neurotoxicity. Abeta plaque burden [43]. Moreover, the increased Abeta deposition and its associated earlier onset and more severe cognitive dysfunction induced by the defect in antioxidant 2. Oxidative Stress and Abeta-Induced Toxicity defense system could be ameliorated by antioxidant supple- Abeta is produced via sequential proteolytic cleavages of mentation [42]. In line with these ndin fi gs, overexpression of manganese superoxide dismutase (MnSOD) in Tg19959 APP by two membrane-bound proteases, beta-secretase, also known as beta-site APP cleaving enzyme 1 (BACE1), and transgenic mice overexpressing APP mutant decreased pro- gamma-secretase, a multiprotein complex consisting of pre- tein oxidation and increased antioxidant defense capability in brains while reducing Abeta plaque burden and restoring the senilin (PS), nicastrin (NCT), anterior pharynx-defective 1 (APH-1), and presenilin enhancer protein 2 (PEN-2) [1, 6, 22]. memory deficit [ 44]. Furthermore, deletion of cytoplasmic BACE1 cleaves APP at the N-terminal end, producing a copper/zinc superoxide dismutase (Cu-Zn-SOD, SOD1) in 99 amino acid APP C-terminal fragment, which is further Tg2576 APP-overexpressing AD mouse model was found to cleaved within the transmembrane domain by gamma- increase Abeta oligomerization while accelerating the loss of secretase, resulting in the release of Abeta peptides [1, 6, 23]. spatial learning and memory as compared with control AD Several peptides of varying lengths can be generated from the mice, suggesting a possible role of oxidative damage in Abeta cleavages by beta- and gamma-secretases; among them, the oligomerization [45]. These results suggest that the enhance- ment of Abeta production/plaque formation as well as Abeta 42-amino acid form of Abeta (Abeta42) is more toxic than the more abundantly produced 40-amino acid form of Abeta oligomerization by oxidative stress is important for the (Abeta40), possibly because of its faster self-aggregation into initiation and development of AD. Studies on how oxidative stress enhances Abeta produc- oligomers [1, 23, 24]. In fact, multiple lines of evidence suggest that soluble Abeta oligomers are the most neurotoxic, whose tion have revealed that oxidative stress decreases the activity levels correlate with the severity of the cognitive decline in of alpha-secretase while promoting the expression and acti- AD [23, 24]. Cleavage of APP by a third enzyme, alpha- vation of beta- and gamma-secretase, enzymes critical for the secretase, precludes the formation of toxic Abeta peptides generation of Abeta from APP [46–50]. The induction of BACE1 and PS1 expression and the activation of gamma- [25]. Increased production and/or decreased clearance of Abeta peptides leads to the accumulation of Abeta, which secretase by oxidative stress were found to be dependent on stimulates diverse cell signaling pathways, eventually result- the activation of c-Jun N-terminal kinase (JNK) pathway, a major cell signaling cascade that is stimulated by oxidative ing in synaptic degeneration, neuronal loss and decline in cognitive function [6, 23, 24, 26–28]. stress [51, 52]. In fact, the promoter and 5 untranslated region A great deal of research has implicated oxidative stress in of BACE gene contain binding sites for multiple transcrip- tion factors including the redox-sensitive activator protein Abeta-induced neurotoxicity [29]. In vitro experiments using cell models showed that Abeta treatment could increase the (AP1) and nuclear factor (NF)-kappa B, activation of which levels of hydrogen peroxide and lipid peroxides [30]. Con- by oxidative stress may in turn enhance BACE expression sistently, in various AD transgenic mouse models carrying [53]. In AD brains, both the activation of JNK signaling mutants of APP and PS-1, increased hydrogen peroxide and cascade [54–56] and the elevation of BACE1 and PS1 expres- sion/activity have been detected [57–59]; thus, it is possible nitric oxide production as well as elevated oxidative modifi- cations of proteins and lipids were correlated with the age- that the increased oxidative stress in AD brains may initiate associated Abeta accumulation, confirming that Abeta pro- the activation of a cascade of redox-sensitive cell signal pathways including JNK, which promotes the expression of motes oxidative stress [31–35]. In hippocampal neuronal cell cultures, the induction of reactive oxygen species (ROS) by BACE1 and PS1, eventually enhancing the production of Oxidative Medicine and Cellular Longevity 3 Abeta and the deterioration of cognitive function. As JNK has cytochrome oxidase (complex IV) activity in the cortical also been implicated in Abeta-induced neuronal apoptosis regions of AD brains was reported [74]. Decfi iency in this key [60], oxidative stress may enhance Abeta production as well electron transport enzyme could lead to the increase in ROS as mediate Abeta-induced neurotoxicity through the activa- production and reduction in energy stores, eventually con- tion of redox-sensitive signaling pathways such as JNK. tributing to the neurodegenerative process [74]. Alternatively, the augmentation of Abeta production by Evidence suggests that Abeta may directly disrupt mito- oxidative stress may be a compensatory reaction to oxidative chondria function and contribute to the deficiency of energy stress. It was found that neuronal oxidative damage was more metabolism and neuronal death seen in AD. It was found pronounced in AD subjects with lesser amounts of Abeta that Abetawas localizedtomitochondriainbrainsofAD deposition or in AD subjects with a shorter disease duration patients and transgenic mice as well as in neuroblastoma cells [61, 62], and there was an inverse relationship between the stably expressing human mutant APP [34, 75]. The presence levels of neuronal oxidative damage to nucleic acids and the of Abeta in mitochondria was associated with impaired amounts of intraneuronal Abeta42 in the hippocampus and mitochondrial metabolism and increased mitochondrial ROS the subiculum of AD brains [63]. These unexpected observa- production [34, 75]. In fact,inisolatedmitochondria, Abeta tionshaveled to thehypothesisthatAbeta maypotentially treatment could cause oxidative injury to mitochondrial play a protective role against neuronal oxidative stress [64]. membrane, disrupt lipid polarity and protein mobility and Indeed, evidence has suggested that picomolar or low inhibit key enzymes of the mitochondria respiratory chain, nanomolar levels of Abeta can be neurotrophic or neuropro- leading to increased mitochondrial membrane permeability tective [65, 66]. Physiological concentrations of Abeta were and cytochrome c release [76, 77]. MnSOD, a primary antiox- shown to efficiently inhibit autooxidation of lipoproteins in idant enzyme protecting mitochondria against superoxide, CSF and plasma [67] and markedly increase hippocampal was found to be a target of nitration and inactivation in a long-term potentiation [68], whereas the high nanomolar double homozygous knock-in mouse model expressing APP concentrations of Abeta caused the well-established toxic and PS-1 mutants [78]. The decreased activity of antioxidant effects. In addition, it appeared that the dualistic eeff cts defense enzymes such as MnSOD may further increase ROS of Abeta depended on the aggregation state of Abeta and levels and compromise mitochondria function, contributing were Abeta size-form specific [ 66, 69]. Taken together, low to the loss of mitochondrial membrane potential and even- levels of Abeta may have a role in the normal function of tually caspase activation and apoptosis [78]. Abeta has also neuronal cells and could beneficially influence the cellular been shown to alter other cellular protective mechanisms redox status, while the abnormal accumulation and aggrega- against oxidative damage to mitochondria. Uncoupling pro- tion of specicfi forms of Abeta, which can be enhanced by teins (UCPs) are a family of mitochondrial anion carrier oxidative stress, may impair neuronal function and further proteins that are located on the inner mitochondrial mem- exacerbate neuronal oxidative damage, contributing to the brane with diverse physiological functions [79]. It has been pathological development of AD. A better understanding of demonstrated that UCP2 and UCP3 can be activated by ROS the pathological as well as the physiological role of Abeta may or products of lipid peroxidation to diminish proton motive lead to more effective strategies for AD interventions. force and reduce mitochondrial membrane potential and ATP production, causing mitochondria uncoupling and de- crease of ROS generation from mitochondria [80]. eTh refore, 3. Mitochondria Dysfunction and Oxidative the expression and activation of UCPs are considered to be Stress in AD a protective mechanism in response to oxidative stress. This Mitochondria are unique organelles that are pivotal for a protective mechanism appears dysfunctional in AD brains variety of cellular functions including ATP synthesis, cal- where the expression of UCP2, 4, and 5 is significantly de- cium homeostasis, and cell survival and death. Meanwhile, creased [81]. In SH-SY5Y neuroblastoma cells overexpressing mitochondrial respiratory chain is a major site of ROS APPorAPP mutant,itwas foundthatthe upregulation of production in thecell, andmitochondriaare particularly UCP2 and UCP4 protein levels in response to the exposure vulnerable to oxidative stress [70, 71]. Extensive studies have of superoxide was abrogated; although the mechanisms are demonstrated that mitochondria dysfunction is an important unclear, it suggests that Abeta accumulation may lead to irreversible cellular alterations that render the cell more factor involved in the pathogenesis of AD. A number of mito- chondrial and metabolic abnormalities have been identified susceptible to oxidative stress [82]. Moreover, the UCP2- and in the hippocampal neurons of AD compared to age-matched UCP4-dependent upregulation of mitochondrial free cal- controls [72–74]. Morphometric analysis of biopsies from AD cium in response to superoxide treatment was found to be brains showed a signicfi ant reduction of mitochondria, while diminished in cells overexpressing APP or APP mutant, indi- the mitochondrial DNA and protein were increased in the cating that the Abeta accumulation may be associated with cytoplasm and in the vacuoles associated with lipofuscin, a a dysfunction of mitochondria as a reserve pool of intracel- lysosome suggested as the site of mitochondrial degradation lular calcium that leads to an increased cell sensitivity to the loss of calcium homeostasis [82]. by autophagy [72, 73]. eTh se mitochondrial abnormalities were foundaccompaniedbyoxidative damage marked by It is noted that the mitochondria-associated Abeta along 8-hydroxyguanosine and nitrotyrosine, indicating that the with the increase in hydrogen peroxide and decrease in cytochrome oxidase activity was detected prior to the appear- mitochondria were damaged during the progression of AD [72]. In line with this, a signica fi nt decrease of mitochondrial ance of Abeta plaques, suggesting the defect in mitochondria 4 Oxidative Medicine and Cellular Longevity +∙ + occurs earlier in the pathogenesis of AD. er Th efore, early forming positively charged Abeta radical (Abeta )[97]. Cu mitochondrially targeted therapeutic interventions may be then donates two electrons to oxygen, generating H O [97, 2 2 effective in delaying the onset and progression of AD [ 34, 75]. 98], settingupconditionstofurther producehydroxylradi- cals (Fenton-type reaction) [99, 100]. After electron donation 2+ to O , the radicalized ⋅Cu complex may be restored to 4. Metal Homeostasis and Oxidative Stress 2+ Abeta⋅Cu by electron transfer from biological reducing in AD agents such as cholesterol, catecholamines, and vitamin C [97]. The efficiency for generation of H O is greater for 2 2 Transition metals such as copper (Cu), zinc (Zn), and iron Abeta42 than Abeta40, correlating with their cytotoxic activ- (Fe) play important catalytic roles in many enzymes and are ity [98, 99]. Similar to copper-Abeta interaction, binding of essential for a broad range of biological processes in human 3+ 2+ Fe to Abeta results in reduction of Fe to Fe and the gener- body including brain functions. Both Cu and Zn have been ation of H O [101]. These data suggest that ROS generated 2 2 shown to participate in regulating synaptic function. Follow- from the interaction of transition metals with Abeta are ing NMDA receptor activation, Cu is released from the neu- key contributors to the oxidative stress in Abeta-mediated ron and regulates neuronal activation by functionally block- neurotoxicity and AD pathogenesis. ing NMDA receptors and limiting calcium entry into the Additionally, there is a close association between Fe/Cu cell [83]. Zn also has a neuromodulatory role; it is released homeostasis and the production and processing of APP. In from presynaptic nerve terminals into the synaptic cleft SH-SY5Y cells overexpressing the Swedish mutant form of upon neuronal activation and has been shown to inhibit humanAPP (APPsw),Fetreatment inducedthe releaseof excitatory NMDA receptors [84]. Fe is crucial for neuronal Abeta42 [102, 103]. Moreover, an iron-responsive element processes such as myelination, synaptogenesis, and synaptic (IRE-Type II) was identified within the 5 -untranslated region plasticity (SP). It is well documented that deficiency of Fe (5 -UTR) of APP transcript, which was selectively downreg- can induce a series of neurochemical alterations that may ulated in response to intracellular Fe chelation; thus, in addi- eventually lead to cognitive deficits [ 85]. While these tran- tion to promotion of Abeta generation from APP, increases sition metals play essential roles in neural functions, their in Fe levels may lead to upregulation of APP protein trans- levels and transport are strictly regulated, as aberrant metal lation through binding of Fe regulatory proteins to the APP homeostasis can result in neurotoxic free-radical production. IRE [104]. On the contrary, Cu treatment was shown to pro- For example, excess Fe or Cu can directly interact with oxygen mote the nonamyloidogenic pathway of APP and decrease the to produce superoxide ion, hydrogen peroxide, and hydroxyl release of Abeta [105]. Thismay be relatedtothe nfi ding that radical, which may lead to oxidative stress and a cascade of Cu is abnormally distributed in AD brain, with accumulation biochemical alterations that eventually cause neuronal cell of Cu in amyloid plaques but a decfi iency of Cu in neighbor- death [86]. In fact, growing evidence has shown that there is a ing cells [87, 88]. close relationship between the disruption of metal home- Studies have shown that metal transporters such as ostasis and AD [86]. Abnormal levels of Cu, Zn, and Fe have been observed in AD hippocampus and amygdala, areas Zn transporters and divalent metal transporter 1 (DMT1) areincreased in thecortexand hippocampusofAPP/PS1 showing severe histopathologic alterations [87]. Moreover, transgenic mice; and similar to transition metals, these metal these transition metals have been detected within the amyloid depositsinADpatientsaswellastransgenicmouse models transporters are colocalized with Abeta in senile plaques in thecortexofADbrains[103, 106, 107]. This leads to the specu- [88–90]. These data suggest that the aberrant accumulation lation that metal transporters may play important roles in the of transition metals may be inextricably linked with Abeta pathology in AD; however, the precise cause and the nature aberrant metal homeostasis in AD. DMT1, also known as nat- ural resistance-associated macrophage protein 2 (Nramp2) or of the involvement of brain metal dyshomeostasis in AD are still largely unknown. divalent cation transporter 1 (DCT1), is a newly discovered proton-coupled metal-ion transport protein responsible for eTh presence of transition metals within the amyloid theuptakeofabroadrange of divalent metalions, including deposits in AD patients indicates that transition metals may 2+ Fe, Cu, and Zn [108]. In APPsw cells, where a significant directly interact with Abeta [88–90]. Indeed, both Cu and 2+ increase in DMT1 levels was found when compared to the Zn can bind to Abeta monomers via three histidine residues 6 13 14 10 control cells [103], it was observed that the intracellular Fe (His ,His ,and His ) and a tyrosine residue (Tyr ), caus- was signicfi antly elevated along with the increased oxidative ing conformational changes of the peptide that promote its stress and cell toxicity [102, 103]. Silencing of endogenous aggregation [91, 92]. Consistently, in vitro data showed that DMT1 by RNA interference (RNAi) decreased the protein Cu and Zn rapidly induced the aggregation of soluble Abeta levels of DMT1 and also reduced bivalent ion influx into peptides [93, 94]. Therefore, the disturbance of metal home- the cells, suggesting that the elevation of DMT1 might be ostasis and the abnormal interactions of Abeta with metal involved in the disruption of Fe homeostasis seen in APPsw ions may be directly involved in the process of Abeta depo- cells [102, 103]. sition in AD brains [93–96]. In addition, the aberrant inter- action between transition metals and Abeta may be a source APP, which has a Cu binding site at N-terminal cysteine- 2+ of ROS generation. Abeta binds Cu with high ani ffi ty, rich region [109], generates free radicals when interacting forming a cuproenzyme-like complex [91]. Electrons can be with Cu.Inaddition,APP hasbeenshown to modulate Cu 2+ + transferred from Abeta to Cu, reducing Cu to Cu and homeostasis. Overexpression of APP in Tg2576 transgenic Oxidative Medicine and Cellular Longevity 5 mice caused a significant reduction in Cu levels [ 110]. In hyperphosphorylation of tau impairs its binding with tubulin APP knockout mice, Cu levels were significantly elevated in and its capacity to promote microtubule assembly, resulting cerebral cortex, a region of the brain particularly involved in its self-aggregation into filaments [ 118]. Anumberofpro- in AD [111, 112]. This leads to the speculation that the tein kinases and protein phosphatases have been implicated secreted APP and/or Abeta may promote the eu ffl x of Cu or in the abnormal phosphorylation of tau including glyco- prevent its uptake, thus reducing its levels [110]. In SH-SY5Y gen synthase kinase-3 beta (GSK-3 beta), cyclin-dependent cells, it was found that endogenous APP had a partial kinase 5, mitogen-activated protein kinase (MAPK), calcium- colocalization with the Golgi marker GM130, while the calmodulin kinase, and protein kinase C [119]. It has been elevation of cellular Cu levels promoted the exit of APP from suggested that the accumulation of Abeta may appear before the Golgi to a wider distribution throughout the cytoplasm the tau pathology and that Abeta aggregates may be one of and to the plasma membrane [113]. It was suggested that the a cascade of molecular events leading to tau hyperphospho- increase in cell surface APP was resulted from a concomitant rayltion [120–122]. On the other hand, it was reported that increase in exocytosis and reduction in endocytosis [113]. overexpression of tau inhibited kinesin-dependent transport The copper-responsive trafficking of APP is therefore con- of peroxisomes, neurofilaments, and Golgi-derived vesicles sistent with a role for APP in Cu eu ffl x pathways [ 111, 113]. into neurites, causing transport defects in primary neuronal These observations suggest that there is an interdependent cells including the tracffi king of APP [ 123]. In particular, relationship between APP metabolism and Cu homeostasis, the transport of APP into axons and dendrites was blocked, perturbationsofeithermay causealterationofthe other, causing its accumulation in the cell body [123]. eventually promoting the accumulation of Abeta and the Although less well studied, evidence has shown that generation of free radicals [112]. oxidative stress is interlinked with tau pathology. It was also As aberrant metal homeostasis plays an important role shown that the cells overexpressing tau protein had increased in several important aspects of AD pathogenesis including susceptibility against oxidative stress, perhaps due to the the production and aggregation of Abeta and the oxidative depletion of peroxisomes [123]. In a drosophila model of stress mediated by Abeta, AD therapy-targeted metal-Abeta human tauopathies expressing a disease-related mutant form interaction is rapidly emerging as a promising therapeutic of human tau (tau R406W), reduction of gene dosage of option. Various metal chelating compounds have been tested thioredoxin reductase (TrxR) or mitochondrial SOD2 for their ecffi acy [ 114]. One of these compounds, clioquinol enhanced tau-induced neurodegenerative histological abnor- (CQ), an orally bioavailable Cu/Zn chelator, was shown to malities and neuronal apoptosis [124]. In contrast, over- 2+ 2+ expression of these antioxidant enzymes or treatment with block Abeta-induced production of H O and Zn /Cu - 2 2 vitamin E attenuated tau-induced neuronal cell death [124]. induced precipitation of synthetic Abeta in vitro and signi-fi Moreover, in cortical neurons derived from a transgenic rat cantly reduce the level of Abeta deposition in brains of Tg2576 model expressing a human truncated variant form of tau transgenic mice [96, 115]. In a randomized, double-blind, protein, it was observed that the levels of ROS were increased placebo-controlled clinical intervention using clioquinol in when compared to control nontransgenic neurons, while patients with moderately severe AD, CQ treatment lowered antioxidants such as vitamin C significantly eliminated the plasma Abeta42 levels and slowed cognitive impairment elevation of ROS [125, 126]. eTh se observations suggest that in the more severely aeff cted patients (baseline cognitive tau-induced neurotoxicity is at least partially mediated by subscale score of the AD Assessment Scale,≥25) during a 36- oxidative damage [124]. The linkage between oxidative week period [116]. stress and tau pathology was further demonstrated in P301S Since the generation of ROS is an important factor in and P301L transgenic mouse models carrying the human AD pathogenesis promoted by the aberrant accumulation of tau gene with P301S or P301L mutations, which exhibit transition metals, natural antioxidants may have protective an accumulation of hyperphosphorylated tau and develop effects against AD pathogenesis induced by disruption of neurob fi rillary tangles and neurodegeneration [ 127]. Mito- metal homeostasis [117]. As expected, treatment with antiox- chondrial dysfunction together with reduced NADH-ubi- idant nicotine attenuated the copper-facilitated neurotoxicity quinone oxidoreductase activity was found in P301L tau induced by Abeta in APPsw cells while decreasing the intra- transgenic mice, which was associated with increased ROS cellular Cu concentration [90]. Consistently, nicotine treat- production, impaired mitochondrial respiration and ATP ment signicfi antly lowered the Cu and Zn concentrations in synthesis in aged animals [128]. Similarly, the brains of senile plaques and a subfield of the hippocampus CA1 region P301S transgenic mice exhibited signs of elevated oxidative in the brains of APPV717I (London mutant form of APP) stress including increased protein carbonyl levels in cortex transgenic mice, and these eeff cts were found to be inde- mitochondria, alterations in the activity and content of pendent of the activation of nicotinic acetylcholine receptors mitochondrial enzymes involved in ROS formation and [90]. These results suggest that antioxidants such as nicotine energy metabolism, suggesting that oxidative stress and mayalsohavearole in regulating metalhomeostasis. mitochondrial dysfunction might play an important role in tau pathology [129]. Consistently, administration of P301S 5. Oxidative Stress and Tau Pathology mice with coenzyme Q10, an antioxidant and a key com- Hyperphosphorylated tau protein is the major component ponent of the electron transport chain, significantly in- creased complex I activity and reduced lipid peroxidation of NFT, another hallmark of AD pathology that correlates with neurodegeneration and cognitive decline [6]. Abnormal while improving survival and behavioral deficits of the mice 6 Oxidative Medicine and Cellular Longevity [130]. Furthermore, the convergence of Abeta and tau and aggregation, decrease of tau phosphorylation and poly- pathologies on mitochondria dysfunction was demonstrated merization, and restoration of mitochondria function and triple metal homeostasis. eTh refore, AD prevention or treatment in a triple transgenic mouse model [pR5/APP/PS2]( AD), withnaturalantioxidantmaybeanapproachthatiscapableof which exhibits both Abeta and tau pathologic features of the targeting a number of different molecular events implicated disease in the brain of the animal [131]. Proteomics analyses triple in the pathogenesis of AD. of the AD brain samples demonstrated a massive dereg- ulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative Acknowledgments phosphorylation system [132]. Notably, deregulation of This work was supported by grants from the National mitochondrial complex IV was shown to be Abeta dependent, Natural Science Foundation of China (30930036, 30870587, while deregulation of complex I was tau dependent [132]. and 31201338) and 973 (2006CB500706). Yan Zhao is The effects of Abeta and tau on mitochondrial function were also supported by the Fundamental Research Funds for found to be synergistic and age associated, resulting in the the Central Universities (HIT.NSRIF.2009147), research decrease of the mitochondrial respiratory capacity and the funds from Harbin Institute of Technology at Weihai reduction of ATP synthesis, which na fi lly led to the synaptic [HIT(WH)Y200902], and Weihai Science and Technology loss, and neuronal death [132]. Development Program (2009-3-93 and 2011DXGJ14). 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