Alzheimer Disease: Moreira PI

Moreira PI, Duarte AI, Santos MS, Rego AC, Oliveira CR. · Center for Neuroscience and Cell Biology, Faculty of Medicine, Institute of Physiology, Department of Zoology, University of Coimbra, Coimbra, Portugal. · J Alzheimers Dis. · Pubmed #19387110 No free full text.

Abstract: The processes underlying the pathogenesis of Alzheimer's disease involve several factors including impaired glucose/energy metabolism, mitochondrial dysfunction, oxidative stress and altered insulin-signaling pathways. This review is mainly devoted to discuss evidence supporting the notion that mitochondrial dysfunction and oxidative stress are interconnected and intimately associated with the development and progression of Alzheimer's disease. Furthermore, the review explores the role of insulin signaling in the pathophysiology of the disease. Indeed, several studies have begun to find links between insulin and mechanisms with clear pathogenic implications for this disorder. Understanding the key mechanisms involved in the etiopathogenesis of Alzheimer's disease may provide opportunities for the design of efficacious preventive and therapeutic strategies.

Su B, Wang X, Nunomura A, Moreira PI, Lee HG, Perry G, Smith MA, Zhu X. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Curr Alzheimer Res. · Pubmed #19075578 No free full text.

Abstract: Multiple lines of evidence demonstrate that oxidative stress is an early event in Alzheimer's disease (AD), occurring prior to cytopathology, and therefore may play a key pathogenic role in AD. Oxidative stress not only temporally precedes the pathological lesions of the disease but also activates cell signaling pathways, which, in turn, contribute to lesion formation and, at the same time, provoke cellular responses such as compensatory upregulation of antioxidant enzymes found in vulnerable neurons in AD. In this review, we provide an overview of the evidence of oxidative stress and compensatory responses that occur in AD, particularly focused on potential sources of oxidative stress and the roles and mechanism of activation of stress-activated protein kinase pathways.

Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. · Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, USA. · Mini Rev Med Chem. · Pubmed #18991755 No free full text.

Abstract: Alzheimer disease treatment has yet to yield a successful therapy that addresses the source of the damage found in brains. Of the varied proposed theories of AD etiology, reactive oxygen species (ROS) generation is cited as a common factor. Efforts to reduce the pathology associated with ROS via antioxidants therefore offer new hope to patients suffering from this devastative disease.

Moreira PI, Santos MS, Oliveira CR, Shenk JC, Nunomura A, Smith MA, Zhu X, Perry G. · Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, 3004-517 Coimbra, Portugal. · CNS Neurol Disord Drug Targets. · Pubmed #18289026 No free full text.

Abstract: Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. All classes of macromolecules (sugar, lipids, proteins, and nucleic acids) are affected by oxidative stress leading, inevitably, to neuronal dysfunction. Extensive data from the literature support the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, it has been suggested that in the initial stages of the development of Alzheimer disease, amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses to ensure that neuronal cells do not succumb to oxidative damage. However, during the progression of the disease, the antioxidant activity of both agents is either overwhelmed or, according to others, evolves into pro-oxidant activity resulting in the exacerbation of reactive species production.

Moreira PI, Nunomura A, Nakamura M, Takeda A, Shenk JC, Aliev G, Smith MA, Perry G. · Center for Neuroscience and Cell Biology, Institute of Physiology-Faculty of Medicine, University of Coimbra, Coimbra, Portugal. · Free Radic Biol Med. · Pubmed #18258207 No free full text.

Abstract: Increasing evidence suggests that oxidative stress is intimately associated with Alzheimer disease pathophysiology. Nucleic acids (nuclear DNA, mitochondrial DNA, and RNA) are one of the several cellular macromolecules damaged by reactive oxygen species, particularly the hydroxyl radical. Because neurons are irreplaceable and survive as long as the organism does, they need elaborate defense mechanisms to ensure their longevity. In Alzheimer disease, however, an accumulation of nucleic acid oxidation is observed, indicating an increased level of oxidative stress and/or a decreased capacity to repair the nucleic acid damage. In this review, we present data supporting the notion that mitochondrial and metal abnormalities are key sources of oxidative stress in Alzheimer disease. Furthermore, we outline the mechanisms of nucleic acid oxidation and repair. Finally, evidence showing the occurrence of nucleic acid oxidation in Alzheimer disease will be discussed.

Nunomura A, Moreira PI, Lee HG, Zhu X, Castellani RJ, Smith MA, Perry G. · Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa 078-8510, Japan. · CNS Neurol Disord Drug Targets. · Pubmed #18220780 No free full text.

Abstract: Neuronal death is a common feature in neurodegenerative diseases including Alzheimer disease (AD) and Parkinson disease (PD). This occurs over years, not the minutes of classically defined apoptosis, and neurons show both responses of apoptosis and regeneration, evidenced by accumulated oxidative insult and attempts at cell cycle re-entry. There is recent evidence suggesting that several known gene mutations in causing familial AD (amyloid beta protein precursor, presenilin-1, or presenilin-2 gene) and familial PD (Parkin, PINK-1, or DJ-1 gene) are associated with increased oxidative stress. Also, several known genetic (e.g. Apolipoprotein Eepsilon4 variant) and environmental (e.g. metals or pesticides exposure) risk factors of sporadic AD and/or PD are associated with increased oxidative stress. In concord, patients at the preclinical stages of AD and PD as well as cellular and animal models of the diseases provide consistent evidence that oxidative insult is a significant early event in the pathological cascade of AD and PD. In contrast to the general aspects of the pathological hallmarks, aggregation of the disease-specific proteins such as amyloid-beta, tau, and alpha-synuclein may act as a compensatory (survival) response against the oxidative insult via the mechanism that the disease-specific structures sequester redox-active metals. Expanding knowledge of the molecular mechanisms of organism longevity indicates that pro-longevity gene products such as forkhead transcription factors and sirtuins are involved in the insulin-like signaling pathway and oxidative stress resistance against aging. An enhancement of the pro-longevity signaling (e.g. caloric restriction) may be a promising approach as anti-oxidative strategy against age-associated neurodegenerative diseases.

Nunomura A, Moreira PI, Takeda A, Smith MA, Perry G. · Department of Psychiatry and Neurology, Asahikawa Medical College, Higashi 2-1-1-1, Midorigaoka, Asahikawa 078-8510, Japan. · Curr Med Chem. · Pubmed #18220733 No free full text.

Abstract: Although cellular RNA should be subject to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigating the magnitude and the biological consequences of the free radical damage. However, because RNA is mostly single-stranded and its bases are not protected by hydrogen bonding and are less protected by specific proteins, RNA may be more susceptible to oxidative insults than DNA. Thereafter, oxidative damage to protein-coding RNA or non-coding RNA will potentially cause errors in proteins or dysregulation of gene expression. While less lethal than mutations in genome, such non-acutely lethal insults to cells might be associated with underlying mechanisms of several human diseases, especially chronic degeneration. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage is a feature in vulnerable neurons at the very earliest-stages of these diseases, suggesting that RNA oxidation may actively contribute to the onset or to the development of disease. Mechanistically speaking, an increasing body of evidence suggests that the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of mechanisms that avoid the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations toward understanding of the consequences and processing mechanisms related to oxidative RNA damage may provide significant insights into the pathogenesis and therapeutic strategies for neurodegenerative and other degenerative diseases.

Moreira PI, Harris PL, Zhu X, Santos MS, Oliveira CR, Smith MA, Perry G. · Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. · J Alzheimers Dis. · Pubmed #17917164 links to  free full text

Abstract: In this study, we evaluated the effect of lipoic acid (LA) and N-acetyl cysteine (NAC) on oxidative [4-hydroxy-2-nonenal, N(epsilon)-(carboxymethyl)lysine and heme oxygenase-1] and apoptotic (caspase 9 and Bax) markers in fibroblasts from patients with Alzheimer disease (AD) and age-matched and young controls. AD fibroblasts showed the highest levels of oxidative stress, and the antioxidants, lipoic acid (1 mM) and/or N-acetyl cysteine (100 microM) exerted a protective effect as evidenced by decreases in oxidative stress and apoptotic markers. Furthermore, we observed that the protective effect of LA and NAC was more pronounced when both agents were present simultaneously. AD-type changes could be generated in control fibroblasts using N-methylprotoporphyrin to inhibit cytochrome oxidase assembly indicating that the the oxidative damage observed was associated with mitochondrial dysfunction. The effects of N-methylprotoporphyrine were reversed or attenuated by both lipoic acid and N-acetyl cysteine. These data suggest mitochondria are important in oxidative damage that occurs in AD. As such, antioxidant therapies based on lipoic acid and N-acetyl cysteine supplementation may be promising.

Moreira PI, Santos MS, Oliveira CR. · Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. · Antioxid Redox Signal. · Pubmed #17678440 No free full text.

Abstract: Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer's disease. Mitochondria are a major source of intracellular reactive oxygen species and are particularly vulnerable to oxidative stress. This review discusses evidence supporting the notion that mitochondrial dysfunction is intimately associated with Alzheimer's disease pathogenesis. Furthermore, the potential connection between mitochondrial dysfunction/oxidative stress and autophagy in Alzheimer's disease is also discussed. As a result of insufficient digestion of oxidatively damaged macromolecules and organelles by autophagy, neurons progressively accumulate lipofuscin (biological garbage) that could exacerbate neuronal dysfunction. The knowledge that mitochondrial dysfunction has a preponderant role in several pathological conditions instigated the development of mitochondrial antioxidant therapies. Mitochondria-targeted antioxidant treatments are briefly discussed in this review.

Castellani RJ, Moreira PI, Liu G, Dobson J, Perry G, Smith MA, Zhu X. · Department of Pathology, University of Maryland, Baltimore, MD, USA. · Neurochem Res. · Pubmed #17508283 No free full text.

Abstract: Although iron is essential in maintaining the function of the central nervous system, it is a potent source of reactive oxygen species. Excessive iron accumulation occurs in many neurodegenerative diseases including Alzheimer disease (AD), Parkinson's disease, and Creutzfeldt-Jakob disease, raising the possibility that oxidative stress is intimately involved in the neurodegenerative process. AD in particular is associated with accumulation of numerous markers of oxidative stress; moreover, oxidative stress has been shown to precede hallmark neuropathological lesions early in the disease process, and such lesions, once present, further accumulate iron, among other markers of oxidative stress. In this review, we discuss the role of iron in the progression of AD.

Castellani RJ, Zhu X, Lee HG, Moreira PI, Perry G, Smith MA. · University of Maryland, Department of Pathology, Baltimore, MD 21201, USA. · Expert Rev Neurother. · Pubmed #17492899 No free full text.

Abstract: Although amyloid-beta-containing senile plaques and phospho-tau containing neurofibrillary tangles are hallmark lesions of Alzheimer disease (AD), neither is specific for AD, nor even a marker of AD. Rather, they are empirical lesions that require close correlation with age and clinical signs for optimal interpretation. In essence, these lesions represent the effect rather than the cause of disease. In this review, we discuss diagnostic criteria for AD, the relationship between pathology, pathogenesis and multiple treatment approaches that have so far been disappointing, including those that presume to address pathological lesions. An acceptance that lesion-based therapies do not address etiology or rate-limiting pathogenic factors is probably necessary for the best chance of significant advances that have thus far been elusive.

Casadesus G, Moreira PI, Nunomura A, Siedlak SL, Bligh-Glover W, Balraj E, Petot G, Smith MA, Perry G. · Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA. · Neurochem Res. · Pubmed #17342408 No free full text.

Abstract: Metabolic alterations are a key player involved in the onset of Alzheimer disease pathophysiology and, in this review, we focus on diet, metabolic rate, and neuronal size differences that have all been shown to play etiological and pathological roles in Alzheimer disease. Specifically, one of the earliest manifestations of brain metabolic depression in these patients is a sustained high caloric intake meaning that general diet is an important factor to take in account. Moreover, atrophy in the vasculature and a reduced glucose transporter activity for the vessels is also a common feature in Alzheimer disease. Finally, the overall size of neurons is larger in cases of Alzheimer disease than that of age-matched controls and, in individuals with Alzheimer disease, neuronal size inversely correlates with disease duration and positively associates with oxidative stress. Overall, clarifying cellular and molecular manifestations involved in metabolic alterations may contribute to a better understanding of early Alzheimer disease pathophysiology.

Zhu X, Smith MA, Honda K, Aliev G, Moreira PI, Nunomura A, Casadesus G, Harris PL, Siedlak SL, Perry G. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neurol Sci. · Pubmed #17337008 links to  free full text

Abstract: Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process.

Moreira PI, Santos MS, Seiça R, Oliveira CR. · Center for Neuroscience and Cell Biology, Institute of Physiology, Faculty of Medicine, University of Coimbra, 3004-354 Coimbra, Portugal. · J Neurol Sci. · Pubmed #17316694 No free full text.

Abstract: It has been argued that in late-onset Alzheimer's disease a disturbance in the control of neuronal glucose metabolism consequent to impaired insulin signalling strongly resembles the pathophysiology of type 2 diabetes in non-neural tissue. The fact that mitochondria are the major generators and direct targets of reactive oxygen species led several investigators to foster the idea that oxidative stress and damage in mitochondria are contributory factors to several disorders including Alzheimer's disease and diabetes. Since brain possesses high energetic requirements, any decline in brain mitochondria electron chain could have a severe impact on brain function and particularly on the etiology of neurodegenerative diseases. This review is primarily focused in the discussion of brain mitochondrial dysfunction as a link between diabetes and Alzheimer's disease.

Liu Q, Xie F, Rolston R, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. · Department of Ophthalmology, University of California-San Diego, 9500 Gilman Drive #0946, La Jolla, CA 92093-0946, USA. · Mini Rev Med Chem. · Pubmed #17305591 No free full text.

Abstract: There is considerable evidence showing that oxidative damage is one of the earliest neuronal and pathological changes of Alzheimer disease and many, if not all, of the etiological and pathological causes of the disease are related, directly or indirectly, to free radical production and oxidative damage. Here we summarize the current body of knowledge suggestive that oxidative damage is, if not the key factor, certainly a major factor in Alzheimer disease. As such, therapeutic modalities encompassing antioxidants may be an effective approach to the treatment of neurodegenerative diseases and delay the aging process.

Zhu X, Perry G, Moreira PI, Aliev G, Cash AD, Hirai K, Smith MA. · Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA. · J Alzheimers Dis. · Pubmed #16873962 No free full text.

Abstract: A number of mitochondrial and metabolic abnormalities were identified in the hippocampal neurons of Alzheimer disease compared to age-matched controls. Hippocampal neurons are the most vulnerable to disease-associated pathology (i.e., cell death and proteinaceous lesions) and contain numerous markers of oxidative stress. Interestingly we found that the levels of mitochondrial DNA and cytochrome oxidase-1 in these neurons are markedly increased compared with those of age-matched control brains, even though the number of mitochondria per neuron is decreased. We hypothesize that the increased levels of mitochondrial DNA and cytochrome oxidase-1 may reflect an attempt by oxidatively-challenged neurons to replicate mitochondria, albeit unsuccessfully, as a response to the energetic/oxidative stress. Indeed, in this context, numerous signs of mitosis are observed in pyramidal neurons. Mitotic signals that promote cell cycle re-entry might be expected to also signal the synthesis of new mitochondria. Alternatively, these abnormalities may indicate altered turnover of mitochondrial components as a result of reduced degradation of mitochondrial byproducts or altered mitochondrial transport that redistributes mitochondrial DNA and cytochrome oxidase-1 to the cell body.

Moreira PI, Cardoso SM, Santos MS, Oliveira CR. · Center for Neuroscience and Cell Biology, Institute of Physiology-Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal. · J Alzheimers Dis. · Pubmed #16873957 No free full text.

Abstract: Mitochondria are uniquely poised to play a pivotal role in neuronal cell survival or death because they are regulators of both energy metabolism and apoptotic pathways. This review is mainly focused in the discussion of evidence suggesting a clear association between amyloid-beta toxicity, mitochondrial dysfunction, oxidative stress and neuronal damage/death in Alzheimer's disease pathophysiology. The knowledge that mitochondrial dysfunction has a preponderant role in Alzheimer's disease opened a window for new therapeutic strategies aimed to preserve/ameliorate mitochondrial function. Based on recent developments in mitochondrial research, increased pharmacological and pharmaceutical efforts have lead to the emergence of 'Mitochondrial Medicine' as a whole new field of biomedical research being this topic discussed in the last section of this review.

Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA. · Department of Psychiatry and Neurology, Asahikawa Medical College, Asahikawa, Japan. · J Neuropathol Exp Neurol. · Pubmed #16825950 No free full text.

Abstract: Genetic and lifestyle-related risk factors for Alzheimer disease (AD) are associated with an increase in oxidative stress, suggesting that oxidative stress is involved at an early stage of the pathologic cascade. Moreover, oxidative stress is mechanistically and chronologically associated with other key features of AD, namely, metabolic, mitochondrial, metal, and cell-cycle abnormalities. Contrary to the commonly held notion that pathologic hallmarks of AD signify etiology, several lines of evidence now indicate that aggregation of amyloid-beta and tau is a compensatory response to underlying oxidative stress. Therefore, removal of proteinaceous accumulations may treat the epiphenomenon rather than the disease and may actually enhance oxidative damage. Although some antioxidants have been shown to reduce the incidence of AD, the magnitude of the effect may be modified by individual factors such as genetic predisposition (e.g. apolipoprotein E genotype) and habitual behaviors. Because caloric restriction, exercise, and intellectual activity have been experimentally shown to promote neuronal survival through enhancement of endogenous antioxidant defenses, a combination of dietary regimen of low total calorie and rich antioxidant nutrients and maintaining physical and intellectual activities may ultimately prove to be one of the most efficacious strategies for AD prevention.

Moreira PI, Zhu X, Nunomura A, Smith MA, Perry G. · Case Western Reserve University, Department of Pathology, Cleveland, Ohio 44106, USA. · Expert Rev Neurother. · Pubmed #16784412 No free full text.

Abstract: Alzheimer's disease (AD) places an enormous burden on individuals, families and society. Consequently, a tremendous effort is being devoted to the development of drugs that prevent or delay neurodegeneration. Current pharmacological treatments are based on the use of acetylcholinesterase inhibitors or memantine, a N-methyl-D-aspartate channel blocker. However, new therapeutic approaches, including those more closely targeted to the pathogenesis of the disease, are being developed. These potentially disease-modifying therapeutics include secretase inhibitors, cholesterol-lowering drugs, amyloid-beta immunotherapy, nonsteroidal anti-inflammatory drugs, hormonal modulation and the use of antioxidants. The possibility that oxidative stress is a primary event in AD indicates that antioxidant-based therapies are perhaps the most promising weapons against this devastating neurodegenerative disorder.

Moreira PI, Zhu X, Liu Q, Honda K, Siedlak SL, Harris PL, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44100, USA. · Biol Res. · Pubmed #16629160 links to  free full text

Abstract: Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. In the first stage of development of the disease, amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. These findings suggest that Alzheimer disease is associated with a novel balance in oxidant homeostasis.

Moreira PI, Zhu X, Lee HG, Honda K, Smith MA, Perry G. · Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA. · Mech Ageing Dev. · Pubmed #16516950 No free full text.

Abstract: Compelling evidence supports the importance of metabolic abnormalities in Alzheimer disease pathogenesis. Indeed, that oxidative mechanisms are involved in the neuropathology associated with Alzheimer disease is evidenced by the large number of metabolic signs of oxidative stress as well as by specific markers of oxidative damage. However, in the initial stages of disease development, neurons adapt to the oxidative environment through the development of compensatory responses resulting in a shift of neuronal priority from normal function to basic survival.

Moreira PI, Honda K, Zhu X, Nunomura A, Casadesus G, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · Neurology. · Pubmed #16432155 No free full text.

Abstract: Neuronal oxidative stress occurs early in the progression of Alzheimer disease (AD), significantly before the development of the pathologic hallmarks, neurofibrillary tangles, and senile plaques. Study of Down syndrome, cases with autosomal dominant mutation, and sporadic AD all suggest amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. Amyloid-beta and tau hyperphosphorylation also define vulnerable muscle cells in sporadic inclusion-body myositis (s-IBM). The role of the structural changes of s-IBM, as in AD, remains to be determined but may mark a critical response yielding a novel balance in oxidant homeostasis.

Moreira PI, Honda K, Liu Q, Santos MS, Oliveira CR, Aliev G, Nunomura A, Zhu X, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Curr Alzheimer Res. · Pubmed #16248845 No free full text.

Abstract: The complex nature and genesis of oxidative damage in Alzheimer disease can be partly answered by mitochondrial and redox-active metal abnormalities. By releasing high levels of hydrogen peroxide, dysfunctional mitochondria propagate a series of interactions between redox-active metals and oxidative response elements. In the initial phase of disease development, amyloid-beta deposition and hyperphosphorylated tau may function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative injuries. However, during the progression of the disease, the antioxidant activity of both agents evolves into pro-oxidant activity representing a typical gain-of-function transformation, which can result from an increase in reactive species and a decrease in clearance mechanisms.

Sayre LM, Moreira PI, Smith MA, Perry G. · Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA. · Ann Ist Super Sanita. · Pubmed #16244388 links to  free full text

Abstract: This review highlights the role of oxidative stress and imbalances in metal ion homeostasis in the neurodegenerative diseases Alzheimer's disease and Parkinson's disease and in the progressive demyelinating disease multiple sclerosis. The chemistry and biochemistry of oxidative stress-induced protein damage are first described, followed by the evidence for a pathological role of oxidative stress in these disease states. It is tempting to speculate that free radical oxygen chemistry contributes to pathogenesis in all these conditions, though it is as yet undetermined what types of oxidative changes occur early in the disease, and what types are secondary manifestations of neuronal degeneration.

Moreira PI, Oliveira CR, Santos MS, Nunomura A, Honda K, Zhu X, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Curr Neurovasc Res. · Pubmed #16181112 No free full text.

Abstract: Oxidative damage is a major feature of Alzheimer's disease pathophysiology. Instead of succumbing to these oxidative abnormalities, neurons upregulate antioxidant defenses, which suggest a novel balance in oxidant homeostasis in Alzheimer's disease. Evidence indicates that in the initial phase of Alzheimer's disease development, amyloid-beta deposition and hyperphosphorylated tau are consequences of oxidative stress and function as a primary line of antioxidant defense. However, during the progression of the disease, the antioxidant activity of both agents evolves into pro-oxidant, representing a typical gain-of-function transformation. This transformation is due to an increase in reactive species and a decrease in clearance mechanisms. However, the notion that amyloid-beta and hyperphosphorylated tau function as protective components in the early stages of Alzheimer's disease brings into serious question the rationale of current therapeutic strategies aimed to remove both amyloid-beta and hyperphosphorylated tau.