Alzheimer Disease: Nunomura A

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.

Castellani RJ, Nunomura A, Lee HG, Perry G, Smith MA. · Department of Pathology, University of Maryland, Baltimore, MD, USA. · J Alzheimers Dis. · Pubmed #18688087 No free full text.

Abstract: Identification of phosphorylated tau as the major protein component of neurofibrillary tangles (NFTs) led to the concept that phosphorylated tau was inherently toxic and, as such, intimately involved in Alzheimer's disease (AD) pathogenesis. While superficially logical, this construct ignores a number of key findings in AD, including i) that NFTs are encountered in viable neurons until late stage disease; ii) that NFTs persist within the neuronal cytoplasm for decades; iii) that NFTs are encountered, sometimes in significant numbers, in cognitively intact elderly; and iv) that neurons with NFTs contain normal content and structure of microtubules. Experimental data in transgenic animal models has further demonstrated that NFTs accumulate in neurons in spite of tau suppression and behavior normalization. These data call into question the inherent toxicity of phosphorylated tau, seemingly leaving the only viable hypothesis of the ad hoc "toxic intermediate" phosphorylated tau concept. However, since we also know that phosphorylated tau sequesters redox active heavy metals and protects against oxidative stress, here we suggest that phosphorylated tau serves a protective role against cellular toxicity.

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.

Imaizumi K, Hara H, Ito Y, Takuma K, Nunomura A. · No affiliation provided · Nippon Yakurigaku Zasshi. · Pubmed #18079598 No free full text.

This publication has no abstract.

Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, Zhu X. · Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · J Alzheimers Dis. · Pubmed #17522439 No free full text.

Abstract: It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer's disease, occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer's disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced Alzheimer's disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer's disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer's disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer's disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.

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.

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.

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.

Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. · Department of Pathology (Neuropathology), University of Maryland, Baltimore, MD, USA. · Acta Neuropathol. · Pubmed #16718346 No free full text.

Abstract: Neuropathological changes in subjects with dementia are, by definition, end-stage phenomena. While such changes allow case characterization and lend themselves to disease classification and modeling, the lesions themselves are not etiological. This truth would appear to be self-evident, yet the medical and scientific literature suggests otherwise. Indeed it is now customary to view amyloid plaques in Alzheimer disease as primary etiological, neurotoxic lesions and, hence, removing them (e.g., by immunotherapy) is believed to lead to clinical improvement. The foundation for this line of thinking lies in the existence of rare kindreds with mutations in amyloid-beta, or mutations believed to be involved in the processing of amyloid-beta, and then the extrapolation of the inherited condition to sporadic disease. We believe that this overall construct ignores early events that are more critical to onset and progression of sporadic disease. Likewise, we have studied subjects with sporadic Alzheimer disease, as well as early onset familial Alzheimer disease and Down's syndrome, over a spectrum of ages, and have found that markers of oxidative stress precede amyloid deposits in all three conditions. Amyloid and neurofibrillary pathology in the Alzheimer brain show a decrease in oxidative stress relative to vulnerable but morphologically intact neurons, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. The pathology of neurodegenerative diseases should be viewed as the end-stage consequence, as opposed to cause, of the disease processes, so that early disease processes that are amenable to intervention can be properly recognized and treated.

Lee HG, Zhu X, Nunomura A, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. · Curr Alzheimer Res. · Pubmed #16472207 No free full text.

Abstract: Alzheimer disease (AD) is a devastating condition and patients, caregivers, clinicians, and scientists are eager to decipher the underlying disease mechanism and, thereafter, target this therapeutically. Most investigators studying the underlying cause of AD have focused on amyloid-beta (Abeta) such that the Amyloid Cascade Hypothesis is the predominant mechanism thought to be responsible for the disease. However, a number of caveats have led us to seriously question the validity of this hypothesis. First, in addition to increases in Abeta, genetic mutations in AD lead to increased vulnerability to oxidative/apoptotic insults indicating that the mutated protein disturbs redox balance. Whether mutations result in Abeta deposition that then causes oxidative stress or whether mutations cause oxidative stress that results in Abeta deposition is unclear. Indeed, while in vitro experiments show that Abeta can directly cause oxidative stress to cells in culture, it is apparent from other studies that the reverse is also true, namely that oxidative stress leads to increases in Abeta. Notably, in vivo studies in both sporadic and genetic forms of the disease show that oxidative stress temporally precedes increases in Abeta and that increases in Abeta are associated with a decrease in oxidative stress. Based on these findings, we herein propose an Alternate Amyloid Hypothesis in which pathogenic factors for disease lead to increased oxidative stress that then leads to increases in Abeta. Further, we propose that Abeta serves as a redox sensor and that oxidatively-induced Abeta serves to attenuate oxidative stress. Obviously, whether Abeta is the culprit, as argued by the Amyloid Cascade Hypothesis, or a much maligned protector, as argued by the Alternate Amyloid Hypothesis, is clearly important to decipher to advance our understanding and design efficacious therapeutics for this disease.

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.

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.

Moreira PI, Smith MA, Zhu X, Nunomura A, Castellani RJ, Perry G. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Ann N Y Acad Sci. · Pubmed #16037277 No free full text.

Abstract: Oxidative stress is a well-studied early response in chronic neurodegenerative diseases, including Alzheimer's disease, where neuronal loss can exceed 90% in the vulnerable neuronal population. Oxidative stress affects all classes of macromolecules (sugar, lipids, proteins, and DNA), leading inevitably to neuronal dysfunction. We observed that Nepsilon-(carboxymethyl)lysine (CML), the predominant advanced glycation end product that accumulates in vivo, along with its glycation-specific precursor hexitol-lysine, are increased in neurons from cases of Alzheimer's disease, especially those containing intracellular neurofibrillary pathology. The increase in hexitol-lysine and CML can result from either lipid peroxidation or advanced glycation, whereas hexitol-lysine is solely a product of glycation, suggesting that two distinct oxidative processes act in concert in the neuropathology of the disease. Furthermore, using olfactory neurons as an experimental model, we observed an increase in glycation products in neurons derived from Alzheimer's disease patients. Our findings support the idea that aldehyde-mediated modifications, in concert with oxyradical-mediated modifications, are critical early pathogenic factors in Alzheimer's disease.

Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106 USA. · Trends Mol Med. · Pubmed #15823754 No free full text.

Abstract: During the past decade, hypotheses concerning the pathogenesis of most neurodegenerative diseases have been dominated by the notion that the aggregation of specific proteins and subsequent formation of cytoplasmic and extracellular lesions represent a harbinger of neuronal dysfunction and death. As such, in Alzheimer's disease, phosphorylated tau protein, the major component of neurofibrillary tangles, is considered a central mediator of disease pathogenesis. We challenge this classic notion by proposing that tau phosphorylation represents a compensatory response mounted by neurons against oxidative stress and serves a protective function. This novel concept, which can also be applied to protein aggregates in other neurodegenerative diseases, opens a new window of knowledge with broad implications for both the understanding of mechanisms underlying disease pathophysiology and the design of new therapeutic strategies.

Liu Q, Lee HG, Honda K, Siedlak SL, Harris PL, Cash AD, Zhu X, Avila J, Nunomura A, Takeda A, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Biochim Biophys Acta. · Pubmed #15615639 No free full text.

Abstract: Fibrillogenesis is a major feature of Alzheimer's disease (AD) and other neurodegenerative diseases. Fibers are correlated with disease severity and they have been implicated as playing a direct role in disease pathophysiology. In studies of tau, instead of finding causality with tau fibrils, we found that tau is associated with reduction of oxidative stress. Biochemical findings show that tau oxidative modifications are regulated by phosphorylation and that tau found in neurofibrillary tangles is oxidatively modified, suggesting that tau is closely linked to the biology, not toxicity, of AD.

Liu Q, Xie F, Siedlak SL, Nunomura A, Honda K, Moreira PI, Zhua X, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Cell Mol Life Sci. · Pubmed #15583867 No free full text.

Abstract: The function of neurofilaments, the major component in large myelinated neurons, is not well understood even though they were discovered as structures over 100 years ago. Recent studies have suggested that neuro-filaments are closely related to many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson disease Alzheimer disease, and diabetes. Using in vitro assays, cultures and transgenic mice, these studies provided new insights into neurofilament function. The function of each subunit, the relationship of neurofilaments with other cytoskeletal elements and their clinical significance are topics of increasing attention.

Castellani RJ, Honda K, Zhu X, Cash AD, Nunomura A, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Ageing Res Rev. · Pubmed #15231239 No free full text.

Abstract: Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology.

Zhu X, Raina AK, Lee HG, Chao M, Nunomura A, Tabaton M, Petersen RB, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Antioxid Redox Signal. · Pubmed #14580312 No free full text.

Abstract: Recent evidence indicates that oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the hallmark pathologies, namely neurofibrillary tangles and senile plaques. The interaction of abnormal mitochondria, redox transition metals, and oxidative stress response elements contributes to the generation of reactive oxygen species in diseased neurons. Oxidative damage to major cellular molecules is seen in a number of disease states that are either acute or chronic and it is apparent that without eliciting compensations that restore redox balance, cells will rapidly succumb to death. Indeed, although oxidative stress is a prominent feature in Alzheimer disease, few vulnerable neurons show clear signs of apoptosis, suggesting that the level of oxidative stress does not significantly exceed neuronal oxidative defenses. In light of this observation, we propose that neurons in Alzheimer disease are exposed to low, but chronic, levels of oxidative stress that lead neurons to elicit adaptive responses such as the activation of stress-activated protein kinase pathways.