Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease

Recent studies of postmortem brains from Alzheimer's disease (AD) patients and transgenic mouse models of AD suggest that oxidative damage, induced by amyloid beta (Abeta), is associated with mitochondria early in AD progression. Abeta and amyloid-precursor protein are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron-transport chain, increase reactive oxygen species production, cause mitochondrial damage and prevent neurons from functioning normally. Furthermore, accumulation of Abeta at synaptic terminals might contribute to synaptic damage and cognitive decline in patients with AD. Here, we describe recent studies regarding the roles of Abeta and mitochondrial function in AD progression and particularly in synaptic damage and cognitive decline.     

Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease

Alzheimer's disease (AD) and cerebrovascular accidents are two leading causes of age-related dementia. Increasing evidence supports the idea that chronic hypoperfusion is primarily responsible for the pathogenesis that underlies both disease processes. In this regard, hypoperfusion appears to induce oxidative stress (OS), which is largely due to reactive oxygen species (ROS), and over time initiates mitochondrial failure which is known as an initiating factor of AD. Recent evidence indicates that chronic injury stimulus induces hypoperfusion seen in vulnerable brain regions. This reduced regional cerebral blood flow (CBF) then leads to energy failure within the vascular endothelium and associated brain parenchyma, manifested by damaged mitochondrial ultrastructure (the formation of large number of immature, electron-dense “hypoxic” mitochondria) and by overproduction of mitochondrial DNA (mtDNA) deletions. Additionally, these mitochondrial abnormalities co-exist with increased redox metal activity, lipid peroxidation, and RNA oxidation. Interestingly, vulnerable neurons and glial cells show mtDNA deletions and oxidative stress markers only in the regions that are closely associated with damaged vessels, and, moreover, brain vascular wall lesions linearly correlate with the degree of neuronal and glial cell damage.We summarize the large body of evidence which indicates that sporadic, late-onset AD results from a vascular etiology by briefly reviewing mitochondrial damage and vascular risk factors associated with the disease and then we discuss the cerebral microvascular changes reason for the energy failure that occurs in normal aging and, to a much greater extent, AD.     

Alzheimer's disease: Effects of β-amyloid on mitochondria

The impairment of the respiratory chain or defects in the detoxification system can decrease electron transfer efficiency, reduce ATP production, and increase reactive oxygen species (ROS) production by mitochondria. Accumulation of ROS results in oxidative stress, a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). β-amyloid has been implicated in the pathogenesis of AD, and its accumulation may lead to degeneration of neuronal or non-neuronal cells. There is evidence that β-amyloid interacts with mitochondria but little is known concerning the significance of this interaction in the physiopathology of AD. This review explores possible mechanisms of β-amyloid-induced mitochondrial toxicity.     

Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease

Alzheimer disease (AD) and Parkinson disease (PD) are the two most common age-related neurodegenerative diseases characterized by prominent neurodegeneration in selective neural systems. Although a small fraction of AD and PD cases exhibit evidence of heritability, among which many genes have been identified, the majority are sporadic without known causes. Molecular mechanisms underlying neurodegeneration and pathogenesis of these diseases remain elusive. Convincing evidence demonstrates oxidative stress as a prominent feature in AD and PD and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD. Notably, mitochondrial dysfunction is also a prominent feature in these diseases, which is likely to be of critical importance in the genesis and amplification of reactive oxygen species and the pathophysiology of these diseases. In this review, we focus on changes in mitochondrial DNA and mitochondrial dynamics, two aspects critical to the maintenance of mitochondrial homeostasis and function, in relationship with oxidative stress in the pathogenesis of AD and PD.     

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

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. Special issue dedicated to Dr. Moussa Youdim.     

The role of iron as a mediator of oxidative stress in Alzheimer disease

Iron is both essential for maintaining a spectrum of metabolic processes in the central nervous system and elsewhere, and potent source of reactive oxygen species. Redox balance with respect to iron, therefore, may be critical to human neurodegenerative disease but is also in need of better understanding. Alzheimer disease (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.     

Increased autophagic degradation of mitochondria in Alzheimer disease

Extensive literature exists supporting a role for mitochondrial dysfunction and oxidative damage in the pathogenesis of Alzheimer disease. Mitochondria are a major source of intracellular reactive oxygen species and are themselves particularly vulnerable to oxidative stress. It has been recently shown that the immunoreactivity of lipoic acid and cytochrome oxidase-1, two mitochondrial markers, is increased in the cytoplasm of pyramidal neurons in Alzheimer disease cases compared with controls. Furthermore, lipoic acid was found to be strongly associated with granular structures and, by ultrastructure analysis, shown to be localized in mitochondria, cytosol and, importantly, in organelles identified as autophagic vacuoles. Lipoic acid was also found associated with the electron dense core of lipofuscin in the brains of Alzheimer disease cases but not in controls, whereas cytochrome oxidase-1 immunoreactivity was limited to mitochondria and cytosol in both Alzheimer and control cases. These data suggest that mitochondria are key targets of increased autophagic degradation in Alzheimer disease. The study of autophagy in Alzheimer disease could clarify the mechanisms underlying this neurodegenerative disorder and, eventually, help in the development of new therapeutic strategies.     

Oxidative stress is responsible for mitochondrial permeability transition induction by salicylate in liver mitochondria

The interaction of salicylate with the respiratory chain of liver mitochondria generates hydrogen peroxide and, most probably, other reactive oxygen species, which in turn oxidize thiol groups and glutathione. This oxidative stress, confirmed by the prevention of action by antioxidant agents, leads to the induction of the mitochondrial permeability transition in the presence of Ca2+. This phenomenon induces further increase of oxidative damage resulting in impairment of oxidative phosphorylation and beta-oxidation, cardinal features of Reye's syndrome in the liver. Mitochondrial permeability transition induction also induces the release of cytochrome c and apoptotic inducing factor from mitochondria, suggesting that salicylate also behaves as a pro-apoptotic agent. The reactive group of salicylate for inducing oxidative stress is the hydroxyl group which, by interacting with a Fe-S cluster of mitochondrial Complex I, the so-called N-2(Fe-S) center, produces reactive oxygen species.     

Targeting NADPH Oxidase and Phospholipases A2 in Alzheimer’s Disease

Alzheimer’s disease (AD) is marked by an increase in the production of extracellular beta amyloid plaques and intracellular neurofibrillary tangles associated with a decline in brain function. Increases in oxidative stress are regarded as an early sign of AD pathophysiology, although the source of reactive oxygen species (ROS) and the mechanism(s) whereby beta amyloid peptides (Aβ) impact oxidative stress have not been adequately investigated. Recent studies provide strong evidence for the involvement of NADPH oxidase and its downstream oxidative signaling pathways in the toxic effects elicited by Aβ. ROS produced by NADPH oxidase activate multiple signaling pathways leading to neuronal excitotoxicity and glial cell-mediated inflammation. This review describes recent studies demonstrating the neurotoxic effects of Aβ in conjunction with ROS produced by NADPH oxidase and the downstream pathways leading to activation of cytosolic phospholipase A₂ (PLA₂) and secretory PLA₂. In addition, this review also describes recent studies using botanical antioxidants to protect against oxidative damage associated with AD. Investigating the metabolic and signaling pathways involving Aβ NADPH oxidase and PLA₂ can help understand the mechanisms underlying the neurodegenerative effects of oxidative stress in AD. This information should provide new therapeutic approaches for prevention of this debilitating disease.     

Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria

Brain accumulation of the amyloid-β peptide (Aβ) and oxidative stress underlie neuronal dysfunction and memory loss in Alzheimer's disease (AD). Hexokinase (HK), a key glycolytic enzyme, plays important pro-survival roles, reducing mitochondrial reactive oxygen species (ROS) generation and preventing apoptosis in neurons and other cell types. Brain isozyme HKI is mainly associated with mitochondria and HK release from mitochondria causes a significant decrease in enzyme activity and triggers oxidative damage. We here investigated the relationship between Aβ-induced oxidative stress and HK activity. We found that Aβ triggered HKI detachment from mitochondria decreasing HKI activity in cortical neurons. Aβ oligomers further impair energy metabolism by decreasing neuronal ATP levels. Aβ-induced HKI cellular redistribution was accompanied by excessive ROS generation and neuronal death. 2-deoxyglucose blocked Aβ-induced oxidative stress and neuronal death. Results suggest that Aβ-induced cellular redistribution and inactivation of neuronal HKI play important roles in oxidative stress and neurodegeneration in AD.     

Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction

Oxidative stress is one of the earliest events in Alzheimer's disease (AD). A chemical genetic screen revealed that deregulated cyclin-dependent kinase 5 (Cdk5) may cause oxidative stress by compromising the cellular anti-oxidant defense system. Using novel Cdk5 modulators, we show the mechanism by which Cdk5 can induce oxidative stress in the disease's early stage and cell death in the late stage. Cdk5 dysregulation upon neurotoxic insults results in reactive oxygen species (ROS) accumulation in neuronal cells because of the inactivation of peroxiredoxin I and II. Sole temporal activation of Cdk5 also increases ROS, suggesting its major role in this process. Cdk5 inhibition rescues mitochondrial damage upon neurotoxic insults, thereby revealing Cdk5 as an upstream regulator of mitochondrial dysfunction. As mitochondrial damage results in elevated ROS and Ca(2+) levels, both of which activate Cdk5, we propose that a feedback loop occurs in late stage of AD and leads to cell death (active Cdk5 --> ROS --> excess ROS --> mitochondrial damage --> ROS --> hyperactive Cdk5 --> severe oxidative stress and cell injury --> cell death). Cdk5 inhibition upon neurotoxic insult prevents cell death significantly, supporting this hypothesis. As oxidative stress and mitochondrial dysfunction play pivotal roles in promoting neurodegeneration, Cdk5 could be a viable therapeutic target for AD.     

Epigenetics,oxidative stress,and Alzheimer disease

Alzheimer disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The sporadic nature of 90% of AD cases, the differential susceptibility to and course of the illness, as well as the late age onset of the disease suggest that epigenetic and environmental components play a role in the etiology of late-onset AD. Animal exposure studies demonstrated that AD may begin early in life and may involve an interplay between the environment, epigenetics, and oxidative stress. Early life exposure of rodents and primates to the xenobiotic metal lead (Pb) enhanced the expression of genes associated with AD, repressed the expression of others, and increased the burden of oxidative DNA damage in the aged brain. Epigenetic mechanisms that control gene expression and promote the accumulation of oxidative DNA damage are mediated through alterations in the methylation or oxidation of CpG dinucleotides. We found that environmental influences occurring during brain development inhibit DNA-methyltransferases, thus hypomethylating promoters of genes associated with AD such as the β-amyloid precursor protein (APP). This early life imprint was sustained and triggered later in life to increase the levels of APP and amyloid-β (Aβ). Increased Aβ levels promoted the production of reactive oxygen species, which damage DNA and accelerate neurodegenerative events. Whereas AD-associated genes were overexpressed late in life, others were repressed, suggesting that these early life perturbations result in hypomethylation as well as hypermethylation of genes. The hypermethylated genes are rendered susceptible to Aβ-enhanced oxidative DNA damage because methylcytosines restrict repair of adjacent hydroxyguanosines. Although the conditions leading to early life hypo- or hypermethylation of specific genes are not known, these changes can have an impact on gene expression and imprint susceptibility to oxidative DNA damage in the aged brain.     

Reactive oxygen species: the unavoidable environmental insult?

Reactive oxygen species (ROS) are generated by a variety of sources from the environment (e.g., photo-oxidations and emissions) and normal cellular functions (e.g., mitochondrial metabolism and neutrophil activation). ROS include free radicals (e.g., superoxide and hydroxyl radicals), nonradical oxygen species (e.g., hydrogen peroxide and peroxynitrite) and reactive lipids and carbohydrates (e. g., ketoaldehydes, hydroxynonenal). Oxidative damage to DNA can occur by many routes including the oxidative modification of the nucleotide bases, sugars, or by forming crosslinks. Such modifications can lead to mutations, pathologies, cellular aging and death. Oxidation of proteins appears to play a causative role in many chronic diseases of aging including cataractogenesis, rheumatoid arthritis, and various neurodegenerative diseases including Alzheimer's Disease (AD). Our goal is to elucidate the mechanism(s) by which oxidative modification results in the disease. These studies have shown that (a) cells from old individuals are more susceptible to oxidative damage than cells from young donors; (b) oxidative protein modification is not random; (c) some of the damage can be prevented by antioxidants, but there is an age-dependent difference; and (d) an age-related impairment of recognition and destruction of modified proteins exists. It is believed that mechanistic insight into oxidative damage will allow prevention or intervention such that these insults are not inevitable. Our studies are also designed to identify the proteins which are most susceptible to ROS damage and to use these as potential biomarkers for the early diagnosis of diseases such as AD. For example, separation of proteins from cells or tissues on one- and two-dimensional gels followed by staining for both total protein and specifically oxidized residues (e.g., nitrotyrosine) may allow identification of biomarkers for AD.     

Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis

The body of evidence from the past three decades demonstrates that oxidative stress can be involved in several diseases. This study aims to summarise the current state of knowledge on the association between oxidative stress and the pathogenesis of some characteristic to the biological systems diseases and aging process. This review also presents the effect of physical activity on redox homeostasis. There is strong evidence from studies for participation of reactive oxygen and nitrogen species in pathogenesis of acute and chronic diseases based on animal models and human studies. Elevated levels of pro-oxidants and various markers of the oxidative stress and cells and tissues damage linked with pathogenesis of cancer, atherosclerosis, neurodegenerative diseases hypertension, diabetes mellitus, cardiovascular disease, atherosclerosis, reproductive system diseases, and aging were reported. Evidence confirmed that inflammation contributes widely to multiple chronic diseases and is closely linked with oxidative stress. Regular moderate physical activity regulates oxidative stress enhancing cellular antioxidant defence mechanisms, whereas acute exercise not preceded by training can alter cellular redox homeostasis towards higher level of oxidative stress. Future studies are needed to clarify the multifaceted effects of reactive oxygen/nitrogen species on cells and tissues and to continue study on the biochemical roles of antioxidants and physical activity in prevention of oxidative stress-related tissue injury.     

Overexpression of frataxin in the mitochondria increases resistance to oxidative stress and extends lifespan in Drosophila

In Friedreich's ataxia, reduction of the mitochondria protein frataxin results in the accumulation of iron and reactive oxygen species, which leads to oxidative damage, neurodegeneration and a diminished lifespan. Recent studies propose that frataxin might play a role in the antioxidative process. Here we show that overexpression of Drosophila frataxin in the mitochondria of female transgenic animals increases antioxidant capability, resistance to oxidative stress insults, and longevity. This suggests that Drosophila frataxin may function to protect the mitochondria from oxidative stresses and the ensuing cellular damage.     

The Saccharomyces cerevisiae Sln1p-Ssk1p two-component system mediates response to oxidative stress and in an oxidant-specific fashion

Aerobic organisms experience oxidative stress due to generation of reactive oxygen species during normal aerobic metabolism. In addition, environmental gamma and UV radiation, as well as several chemicals also generate reactive oxygen species, which induce oxidative stress. Thus oxidative stress constitutes a major threat to organisms living in aerobic environments. Oxidative stress induces the expression of several genes in yeast Saccharomyces cerevisiae. However, the primary sensor(s) that trigger the response is unknown. This study demonstrates that primary sensors of osmotic stress, the Sln1p-Ssk1p two-component proteins, are involved in sensing oxidative stress specifically induced by hydrogen peroxide and diamide, but not by other oxidants used in the study. Wild type and sln1-ssk1 mutant were treated with hydrogen peroxide, diamide, menadione, UV, and gamma-radiation. Results show that sln1-ssk1 mutant is only sensitive to hydrogen peroxide and diamide but not to other oxidants. S. cerevisiae contains an additional cell surface osmosensor, Sho1p, that targets the osmotic signal to Hog1p. Data is presented that shows Sho1 and Hog1 proteins are also involved in signaling oxidant-specific cellular damage. Furthermore, it is demonstrated that expression of the mammalian homolog of Hog1p provides protection from oxidative stress induced by hydrogen peroxide. These results suggest that Sln1p-Ssk1p and Sho1p signal transduction pathways participate in oxidative stress response. However, this response to oxidative stress is limited to specific oxidants.