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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD Since oxidative damage is a key phenomenon in Alzheimer's disease, treatment with antioxidants seems to be a promising approach for slowing disease progression. Oxidative Damage and Alzheimer's Disease: Are Antioxidant Therapies Useful? by Paula I. Moreira, Mark A. Smith, Xiongwei Zhu, Kazuhiro Honda, Hyoung-gon Lee, Gjumrakch Aliev and George Perry Summary Oxidative stress is a key factor involved in the development and progression of Alzheimer's disease, and it is well documented that free radical oxidative damage, particularly of neuronal lipids, proteins, nucleic acids and sugars, is extensive in brains of Alzheimer's disease patients. However, oxidative stress may elicit compensatory responses and downstream adaptations such as amyloid-β deposition and neurofibrillary tangle formation, which may function as "shields" to ensure that neuronal cells do not succumb to oxidative injuries. Although during the past several years our understanding of the mechanisms leading to neuronal damage and death in the course of Alzheimer's disease has improved significantly, we have not found an effective therapeutic to fight this devastating disorder. However, the results obtained in clinical trials with antioxidants are promising and propel us in the search of new and more effective antioxidant therapies. © 2005 Prous Science. All rights reserved. Alzheimer's disease is a progressive disorder that leads to dementia and affects approximately 10% of the population older than 65 years of age. Memory loss is the first sign of cognitive impairment, followed by behavioral disturbances. These symptoms are explained by a severe neuronal loss and the presence of two brain lesions, senile plaques and neurofibrillary tangles (NFT), which are mainly constituted of amyloid-β and hyperphosphorylated tau, respectively.1,2 Alzheimer's disease is devastating, and despite great strides in recent years, still puzzling in its causes and mechanisms. However, it is now well accepted that the mere presence of senile plaques and NFT in Alzheimer's disease does not dictate that they lead to the clinical aspects of the disease, nor that they cause the other cellular changes. Moreover, Alzheimer's disease lesions appear to be downstream of other cytopathological alterations, and instead of being detrimental, they may represent potential protective responses engaged by injured neurons. This idea is supported by evidence showing that increased oxidative damage is a prominent and early feature of vulnerable neurons in Alzheimer's disease.3,4 Current therapeutic targets are centered upon arresting the formation of senile plaques and NFT. However, the validity of such approaches is becoming increasingly questioned due to the potential protective role of Alzheimer's disease lesions. Until this moment, antioxidant strategies seem to be the most encouraging therapeutics, since "fighters" of oxidative stress are effective in reducing the clinical manifestation and evolution of Alzheimer's disease. Oxidative stress and Alzheimer's disease The classic definition of oxidative stress is the imbalance between the generation of reactive oxygen (ROS) and nitrogen species (RNS) and antioxidant defenses. Inherent in this definition is that oxidative stress is an unstable situation and, if there is net damage, the viability of the systems decreases with time, leading to disequilibria and death. However, the classic definition does not fit well in physiological situations or chronic diseases closely aligned to normal physiology, such as Alzheimer's disease. Instead of radicals breaching antioxidant defenses, we propose an altered homeostatic balance resulting from oxidant insult as characteristic of Alzheimer's disease and likely other chronic degenerative diseases. The complex nature and genesis of oxidative damage responses in Alzheimer's disease can perhaps now be partly answered by mitochondrial abnormalities and upregulation of redox- active transition metals that can initiate oxidative stress. A large body of evidence exists demonstrating that there are several abnormalities in the mitochondrial ge- nome5 or deficiencies in key mitochondrial metabolic enzymes6,7 associated with Alzheimer's disease. A common 5 kb deletion in mitochondrial DNA has been shown to increase in Alzheimer's disease patients when compared with controls.8 Additionally, when this deletion was ultrastructurally localized, it was found mainly in abnormal mitochondria that were swollen, lacking cristae and, in some cases, fused with lipofuscin. Dysfunctional mitochondria are a potent source of ROS, particularly superoxide and hydrogen peroxide. These species can react with iron via the Fenton reaction to produce hydroxyl radicals, an extremely reactive and harmful molecule.9 The role of mitochondria in Alzheimer's disease was studied in our laboratory using in situ hybridization to mitochondrial DNA, immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there were mitochondrial abnormalities in Alzheimer's disease.10,11 We found that the neurons showing increased oxidative damage in Alzheimer's disease also possess a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm, and in the case of mtDNA, the vacuoles associated with lipofuscin, whereas morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. We also observed an overall reduction in microtubules in Alzheimer's disease compared to controls.12 Altogether these data are consistent with abnormal mitochondrial turnover, as indicated by increased perikaryal mtDNA and mitochondrial protein accumulation in the face of reduced numbers of mitochondria, and could be due to a defective microtubule metabolism resulting in deficient mitochondrial transport. This may, in turn, set up a pathological cascade of events in the perikaryal mitochondria in which degradation products of mitochondria accumulate in the neuronal cell body. Furthermore, immunocytochemical detection of 8-hydroxy-2-deoxyguanosine (8OhdG) and 8-hydroxyguanosine (8OHG) showed that the increase in DNA and RNA oxidation is limited to the cell bodies of vulnerable neurons in Alzheimer's disease brain.13,14 Another important source of oxidative stress in Alzheimer's disease is the dysregulation of redox-active transition metals homeostasis, especially iron and copper. The imbalance of these two metals is particularly important considering that they are involved in a number of oxidative processes similar to those associated to Alzheimer's disease lesions3,15,16 and to nucleic acids damage.13,14 Fe(III) and Cu(II) are significantly elevated in Alzheimer's disease neuropil and even further concentrated within the core and periphery of senile plaques.17 Additionally, redox-active iron is significantly associated with both senile plaques and NFT in Alzheimer's disease.3 The association of iron with NFT may be partly related to the binding of iron to their primary protein constituent, tau.18 Studies from our lab-oratory demonstrated that specific chelators for copper and iron are able to eliminate redox activity in Alzhei-mer's disease lesions, suggesting that these metals, bound to the lesions, are a major source of ROS.3 Over the past decade, oxidative stress-associated modifications of biological macromolecules has been described in association with the susceptible neurons of Alzheimer's disease: 1) DNA and RNA oxidation is marked by increased levels of 8OhdG and 8OHG;14,19,20 2) protein oxidation is marked by elevated levels of protein carbonyl and widespread nitration of tyrosine residues.4,21 Moreover, crosslinking of proteins, by oxidative processes, may lead to the resistance of the lesions to intracellular and extracellular removal even though they are extensively ubiquitinated,22 and this resistance of NFT to proteolysis might play an important role in the progression of Alzheimer's disease;23 3) lipid peroxidation is marked by higher levels of thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), 4-hydroxy-2-trans-nonenal (HNE) and isoprostanes and altered phospholipid composition.24 Modification to sugars is marked by increased glycation and glycoxidation.25-27 Levels of these markers are initially elevated following some unknown triggering neuronal event, but these levels soon decrease as the disease progresses to advanced Alzheimer's disease.28 These findings suggest that increased oxidative damage is not the terminal sequelae of the disease but instead plays an initial role. They also suggest that damage does not mark further destruction by ROS and is instead marked by a broad array of increased cellular defenses.28 It can be argued that in Alzheimer's disease these defenses are responsible for the reduction of damage if we view Alzheimer's disease in isolation. However, when seen in the context of other conditions where ROS are involved and damage is either limited or absent, such as Parkinson's disease, this result leads us to consider whether oxidative damage noted in Alzheimer's disease may be better thought of as homeostatic, i.e., that oxidative damage could initiate signal transduction pathways to manipulate cellular responses to stress, which is characterized by increased levels of ROS.28 Are Alzheimer's disease lesions compensatory responses against oxidative damage? At the same time oxidative damage was established in Alzheimer's disease, the putative source of ROS was supposed to be the lesions. However, evidence supports the idea that in the early stages of Alzheimer's disease, amyloid-β and hyperphosphorylated tau possess protective/antioxidant properties. An antioxidant role for amyloid-β in vivo is in agreement with recent data on the distribution of oxidative damage to Alzheimer's disease neurons. 8OHG markedly accumulates in the cytoplasm of cerebral neurons in Alzheimer's disease. Unexpectedly, an increase in amyloid-β deposition in Alzheimer's disease cortex is associated with a decrease in neuronal levels of 8OHG, i.e., with decreased oxidative damage.13,14 Similar negative correlation between amyloid-β deposition and oxidative damage is found in patients with Down syndrome.19 Amyloid-β deposits observed in both studies consist mainly of early diffuse plaques, meaning that these diffuse amyloid plaques may be considered as a compensatory response that reduces oxidative stress.9 The strong chelating properties of amyloid-β for zinc, iron and copper explain the reported enrichment of these metals in amyloid plaques in Alzheimer's disease17 and suggest that one function of amyloid-β is to sequester these metal ions. Chelation of transition metals in a redox-inactive form may theoretically serve to inhibit metal-catalyzed oxidation of biomolecules. Methionine at residue 35 on amyloid-β sequence can both scavenge free radicals29 and reduce metals to their high-active low-valency form,30 thereby possessing both anti- and pro-oxidative properties. Reduced metal ions are highly active oxidants and can catalyze further oxidation of biomolecules. For instance, they produce highly reactive hydroxyl radicals from hydrogen peroxide, an important byproduct of mitochondria electron transport chain.31 These data indicate that amyloid-β is a lipophilic metal chelator with a metal-reducing activity. However, an intricate combination of metal chelation, metal reduction and radical scavenging can thus be expected to govern the overall activity of amyloid-β towards oxidation, which may basically embrace the full spectrum of anti- and pro-oxidative effects. However, to induce oxidation amyloid-β requires three important conditions: fibrillation and the presence of transition metals and methionine on residue 35. Indeed, amyloid-β must be present in a relatively high concentration (micromolar range) and the aggregation and fibrillation of amyloid-β occurs only if the peptide is "aged".32,33 The presence of transition metals is a requisite for amyloid-β aggregation and its pro-oxidative activity.34-36 The toxicity of amyloid-β is likely to be mediated by a direct interaction between this peptide and transition metals with subsequent generation of ROS.36,37 Another factor essential for the pro-oxidative activity of amyloid-β seems to be the presence of methionine on residue 35. It has been demonstrated that the substitution of this residue by another amino acid abrogates or significantly diminishes the prooxidant action of amyloid-β.38-40 Methionine 35 can scavenge free radicals41 and reduce transition metals to their high-active low-valency form,42 thereby exhibiting both anti- and pro-oxidative properties. In the adult human brain, tau proteins are found essentially in neurons. Tau proteins bind microtubules through the microtubule-binding domains, and this assembly depends partially upon the degree of phosphorylation, since hyperphosphorylated tau is less effective than hypophosphorylated tau on microtubule polymerization.43 Besides the role in microtubule stabilization, tau has other functions, such as membrane interactions or anchoring of enzymes.44,45 Among the 80 Ser/Thr residues on tau, at least 30 phosphorylation sites have been described, most of which occur on Ser-Pro and Thr-Pro motives. In fact, phosphorylation of Ser262, located in the first microtubule-binding domain, dramatically reduces the affinity of tau for microtubules in vitro.46 Nevertheless, this site alone is insufficient to abolish tau binding to microtubules. Thus, phosphorylation outside the microtubule-binding domains may also strongly influence tubulin assembly by modifying the affinity between tau and microtubules. By regulating microtubule assembly, tau has a role in modulating the functional organization of the neuron, and particularly in axonal morphology, growth and polarity.43 In Alzheimer's disease, hyperphosphorylated tau accumulates in neurons, aggregates into paired helical filaments, and loses its microtubule-binding and stabilizing function, leading to neuronal degeneration.47 However, there is evidence indicating that hyperphosphorylated tau exerts protective functions. It has been shown that oxidative stress and the modification of tau by products of oxidative stress48 leads to protein aggregation (NFT). Further, it has been suggested that neurons with NFT survive decades.49 Neurofilament and tau proteins appear adapted to oxidative stress due to their high content of lysine-serine-proline (KSP) domains.50 Intriguingly, although neurofilament heavy subunit has a long half-life, the same extent of carbonyl modification is found throughout the normal aging process as well as along the length of the axon50 suggesting that oxidative stress-modified molecules are under tight regulation. These molecules may work as buffers by absorbing lipoxidation-derived and glycoxidation-derived aldehydes. Since phosphorylation plays a pivotal role in redox balance, it is perhaps not surprising that oxidative stress, through activation of mitogen-activated protein (MAP) kinase pathways, leads to phosphorylation.51-53 Changes such as MAP kinase and heme oxygenase-1 may be a few of many responses that interrelate to lipid peroxidative modification. Seen as such, oxidative damage is no longer an end-stage event but rather a signal of an underlying change of state. While more studies are required to understand the role of these oxidative modifications in neuronal homeostasis, it is tempting to consider them as augmentations to the neuronal defenses important in protecting the axon. The slow turnover rate of proteins in the axon, which can take years, may necessitate this protection. Should therapeutics be focused on Alzheimer's disease lesion removal? Given the known neuroprotective functions promoted by amyloid-β and t in the early stages of Alzheimer's disease, it seems that the removal of amyloid-β and t would also remove the neuroprotection afforded by both proteins. Indeed, amyloid-β vaccination therapy in human clinical trials has not proven successful, instead leading to clinical signs of neuroinflammation.54,55 These results, taken together with the known function of amyloid-β and t, suggest that any strategy aimed solely at removing both proteins will result in the loss of neuroprotection afforded by these elements in early stages of Alzheimer's disease and induce subsequent side effects. Antioxidant therapies Accumulating evidence from both animal and human studies indicates a major role for oxidative damage in the pathogenesis of Alzheimer's disease.9,28,56-58 These findings raised the possibility of preventing, or at least slowing down, the progression of Alzheimer's disease by the use of antioxidants. A variety of antioxidants exist but only a small number have been formally studied in clinical trials in patients with Alzheimer's disease. However, both in vitro and animal studies suggest that treatment with antioxidant agents may be useful in neurological disorders, including Alzheimer's disease.59 Recently, Polidori et al.60 performed a study that included 63 Alzheimer's disease patients, 23 patients with vascular dementia and 55 controls. They measured plasma levels of water-soluble (vitamin C and uric acid) and lipophilic (vitamin E, vitamin A, carotenoids including lutein, zeaxanthin, β-cryptoxanthin, lycopene, α- and β-carotene) antioxidant micronutrients as well as levels of biomarkers of lipid peroxidation (MDA) and protein oxidation (protein carbonyls and dityrosine) in patients and controls. With the exception of β-carotene, all antioxidants were lower in demented patients as compared to controls. Furthermore, Alzheimer's disease patients showed a significantly higher dityrosine content as compared to controls. Alzheimer's disease and vascular dementia patients showed similar plasma levels of antioxidants and MDA as well as similar content of protein carbonyls and dityrosine. This study suggests that, independent of its nature, vascular or degenerative, dementia is associated with depletion of a large spectrum of antioxidant micronutrients and with increased protein oxidative modification. Similarly, Sano et al.61 reported that vitamin E (a chain-breaking lipid soluble antioxidant) and selegiline (a selective monoamine oxidase type b inhibitor with antioxidant properties) appeared to be beneficial in patients with moderately severe Alzheimer's disease by delaying the time of progression to severe dementia, loss of ability to perform activities of daily living, institutionalization or death. However, it was observed that both treatments given together had no additional benefit over either alone. Other studies on the effect of vitamin E supplementation in Alzheimer's disease subjects have yielded interesting results.61 Those subjects supplemented with 2000 IU per day had a delayed time before they became institutionalized, but supplementation had no effect on loss of cognitive performance. Engelhart and colleagues62 performed a study aimed to determine if dietary antioxidants such as vitamins C, E, β-carotene and flavonoids can help prevent Alzheimer's disease by reducing oxidative stress. The study involved 5395 men and women aged 55 years or older who were free of dementia at the beginning of the study in 1990-1993. During 6 years of follow-up, 197 participants developed dementia, of which 146 cases were diagnosed as Alzheimer's disease. After adjusting for age, sex, alcohol intake, education, smoking status, body mass index, total energy intake and mental examination score at baseline, the researchers concluded that a high intake of vitamins C and E was associated with a lower risk of Alzheimer's disease. Recently, a cross-sectional and prospective study indicated that the use of vitamins E and C supplements in combination is associated with reduced prevalence and incidence of Alzheimer's disease.63 However, Laurin et al.64 observed that mid-life intake of β-carotene, flavonoids and vitamins E and C were not associated with the risk dementia or its subtypes. Data were obtained from the Honolulu-Asia Aging Study, a prospective community-based study of Japanese-American men who were aged 45-68 years in 1965-1968, when 24 h dietary recall was administered. The analysis included 2459 men with complete dietary data who were dementia-free at the first assessment in 1991-1993 and were examined up to two times for dementia between 1991-1993. The sample included 235 incident cases of dementia (102 cases of Alzheimer's disease, 38 cases of Alzheimer's disease with contributing cerebrovascular disease and 44 cases of vascular dementia). α-Lipoic acid is a coenzyme for mitochondrial pyruvate and α-ketoglutarate dehydrogenases. It is a powerful antioxidant and can recycle other antioxidants such as vitamins C, E and glutathione.65 It was reported that old rats supplemented with (R)-α-lipoic acid showed an improvement of mitochondrial function, decreased oxidative damage, and increased metabolic rate.66 Accordingly, Suh et al.67 reported that old rats injected with (R)-α-lipoic acid presented an improvement in reduced glutathione redox status of both cerebral and myocardial tissues when compared with control rats. However, Frölich et al.68 reported that (R)-α-lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer's disease. Gingko biloba contains a variety of components, including flavonoids and terpenoids, which have free radical scavenging ability. Recently, Stackman and colleagues69 tested the ability of Gingko biloba to antagonize the age-related behavioral impairment and neuropathology exhibited by Tg2576, a transgenic mouse model for Alzheimer's disease. They observed that transgenic mice treated with Gingko biloba exhibited spatial memory retention comparable to wild-type mice. However, there were no differences in soluble amyloid-β and hippocampal amyloid-β plaque burden between treated and untreated TG2576 mice. Paradoxically, the levels of protein carbonyls were increased in Gingko biloba-treated mice. Colciaghi et al.70 investigated the effect of Egb761, an extract of Gingko biloba, on amyloid-β protein precursor (AβPP) metabolism both in vitro and in vivo models. To this aim, α-secretase, the enzyme regulating the non-amyloidogenic processing of AβPP, and the release of αAβPPs, the α-secretase metabolite, were studied in superfusates of hippocampal slices after Egb761 incubation, and in hippocampi and cortices of Egb761-treated rats. They observed that Egb761 increases αAβPPs release through a protein kinase C-independent manner. This effect was not accompanied by a modification of either AβPP forms or α-secretase expression. Moreover, Egb761 influence on αAβPPs release was strictly dependent on treatment dosage. Their findings suggest that the benefit of Egb761 is underscored by a specific biological mechanism of this compound on AβPP metabolism, directly affecting the release of the non-amyloidogenic metabolite. In a randomized controlled trial, EGb716, an extract of Gingko biloba, was examined in 327 patients, 45 years or older, with mild to severe dementia resulting from either Alzheimer's disease or vascular dementia.71 In this study, 150 Alzheimer's disease patients were included and half received placebo for 1 year. Patients in the active treatment group had a significantly higher score on the Alzheimer's Assessment Scale-Cognitive Subscale (ADAS-Cog), a measure of cognitive impairment, and in improved Geriatric Evaluation by Relative's Rating Instrument (GERRI) score, a measure of daily living and social behavior. However, there was no difference between groups in the Clinical Global Impression of Change, an interview-based global rating that quantifies the clinician's judgment of the amount of change in overall impairment compared with baseline. They also do not present any difference concerning the number or severity of adverse events between patients given extract or placebo. However, these findings suggest that Gingko biloba may be beneficial in patients with Alzheimer's disease and vascular dementia. Given the importance of oxidative stress in Alzheimer's disease pathophysiology, antioxidants may prove to be therapeutic. However, the broad occurrence of the disease (almost 50% by the age of 85), the nonregenerative nature of the CNS and the fact that diagnosis often does not occur until late in disease progression suggest that the ideal antioxidant should be used as prophylactic treatment in aged population. Due to their low toxicity, low cost and their ability to target the earliest sources of oxidative stress in Alzheimer's disease, antioxidant therapies are particularly attractive. Conclusions There is now convincing evidence that oxidative stress is intimately involved in the onset and progression of Alzheimer's disease. Furthermore, brains of Alzheimer's disease patients show a significantly greater degree of macromolecule oxidation when compared to age-matched control individuals. In this line, the causes and consequences of neuronal damage should be properly identified, not only to elucidate the mechanistic basis of Alzheimer's disease but also for the development of new therapeutic strategies. Since oxidative damage is a key phenomenon in Alzheimer's disease, treatment with antioxidants seems to be a promising approach for slowing disease progression to the extent that oxidative damage may be responsible for the cognitive and functional decline observed in Alzheimer's disease. References 1. Khachaturian, Z.S. Diagnosis of Alzheimer's disease. Arch Neurol 1985, 42: 1097- 105. 2. Mirra, S.S., Heyman, A., McKeel, D. et al. The consortium to establish a registry for Alzheimer's disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. 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Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment. Exp Neurol 2003, 184: 510-20. 70. Colciaghi, F., Borroni, B., Zimmermann, M. et al. Amyloid precursor protein metabolism is regulated toward alpha-secretase pathway by Ginkgo biloba extracts. Neurobiol Dis 2004, 16: 454-60. 71. Le Bars, P.L., Katz, M.M., Berman, N., Itil, T.M., Freedman, A.M. and Schatzberg, A.F. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997, 278: 1327-32. Paula I. Moreira is a Graduate Student at the Institute of Pathology, Case Western Research University, Cleveland, Ohio, U.S.A., and the Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, Coimbra, Portugal. Mark A. Smith, Xiongwei Zhu, Kazuhiro Honda, Hyoung-gon Lee, Gjumrakch Aliev and George Perry are Postdoctoral Fellows and Faculty at the Institute of Pathology, Case Western Research University, Cleveland, Ohio, U.S.A. Correspondence: George Perry, Ph.D., Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. Tel: 216-368-2488, Fax: 216-368-8964; E-mail: george.perry@case.edu. Drug News & Perspectives
Vol. 18, No. 1, 2005, pp. 13-19
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