Mitochondrial failures in Alzheimer's disease

Mitochondrial dysfunction and free radical-induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Alzheimer's disease (AD). The defective adenosine triphosphate (ATP) production and increased oxygen radicals may induce mitochondria-dependent cell death because damaged mitochondria are unable to maintain the energy demands of the cell. The role of vascular hypoperfusion-induced mitochondria failure in the pathogenesis of AD now has been widely accepted. However, the exact cellular mechanisms behind vascular lesions and their relation to oxidative stress markers identified by RNA oxidation, lipid peroxidation, or mitochondrial DNA (mtDNA) deletion remain unknown. Future studies comparing the spectrum of mitochondrial damage and the relationship to oxidative stress-induced damage during the aging process or, more importantly, during the maturation of AD pathology are warranted.     

PLA2G3, a gene involved in oxidative stress induced death, is associated with Alzheimer's disease

Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging, the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking such stress in AD brains, are therefore of great interest. PLA2G3 is the most overexpressed gene in a human neuronal model of oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system, which provokes apoptotic cell death. In this work, we describe that PLA2G3 gene silencing produced a marked inhibition of X-XOD induced cell death, and that PLA2G3 polymorphisms are associated with AD in a Spanish case-control sample. The capacity to respond to oxidative stress may therefore modulate the risk of AD, and PLA2G3 is a potential target to regulate neuronal damage induced by free radicals.     

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.     

Elevation of mitochondrial glutathione by gamma-glutamylcysteine ethyl ester protects mitochondria against peroxynitrite-induced oxidative stress

Mitochondria under oxidative stress are thought to play a key role in various neurodegenerative disorders by directing neurons to cell death. Protection by antioxidants against oxidative stress to mitochondria may prove to be beneficial in delaying onset or progression of these diseases. We have investigated the ability of gamma-glutamylcysteine ethyl ester (GCEE) to upregulate mitochondrial glutathione (GSH) in vivo or in vitro and protect against subsequent in vitro peroxynitrite (ONOO-) damage. Mitochondria pretreated in vitro with GCEE were protected against oxidative damage induced by peroxynitrite, as assessed by mitochondrial swelling, changes in mitochondrial membrane potential, 3-nitrotyrosine formation, protein carbonyl formation, and cytochrome c release. Loss of mitochondrial function in neuronal cell cultures by the oxidants 2,2,'Azobis(2-amidino-propane)dihydrochloride (AAPH) and ONOO- was ameliorated by treatment with GCEE. In vivo studies showed that mitochondria isolated from animals injected intraperitoneally with GCEE were protected partially against oxidative modifications induced by ONOO-. Taken together, these results suggest that GCEE may be effective in increasing mitochondrial GSH and may be prove to have therapeutic relevance in neurodegenerative disorders associated with oxidative stress and mitochondrial dysfunction.     

Release of mitochondrial Opa1 following oxidative stress in HT22 cells

Cellular mechanisms involved in multiple neurodegenerative diseases converge on mitochondria to induce overproduction of reactive oxygen species, damage to mitochondria, and subsequent cytochrome c release. Little is currently known regarding the contribution mitochondrial dynamics play in cytochrome c release following oxidative stress in neurodegenerative disease. Here we induced oxidative stress in the HT22 cell line with glutamate and investigated key mediators of mitochondrial dynamics to determine the role this process may play in oxidative stress induced neuronal death. We report that glutamate treatment in HT22 cells induces increase in reactive oxygen species (ROS), release of the mitochondrial fusion protein Opa1 into the cytosol, with concomitant release of cytochrome c. Furthermore, following the glutamate treatment alterations in cell signaling coincide with mitochondrial fragmentation which culminates in significant cell death in HT22 cells. Finally, we report that treatment with the antioxidant tocopherol attenuates glutamate induced-ROS increase, release of mitochondrial Opa1 and cytochrome c, and prevents cell death.     

Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich's ataxia

There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration. The precise sequence of events in FRDA pathogenesis is uncertain. The impaired intramitochondrial metabolism with increased free iron levels and a defective mitochondrial respiratory chain, associated with increased free radical generation and oxidative damage, may be considered possible mechanisms that compromise cell viability. Recent evidence suggests that frataxin might detoxify ROS via activation of glutathione peroxidase and elevation of thiols, and in addition, that decreased expression of frataxin protein is associated with FRDA. Many approaches have been undertaken to understand FRDA, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to FRDA pathogenesis. Brains of FRDA patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress. In the central nervous system, heat shock protein (HSP) synthesis is induced not only after hyperthermia, but also following alterations in the intracellular redox environment. The major neurodegenerative diseases, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's disease (HD) and FRDA are all associated with the presence of abnormal proteins. Among the various HSPs, HSP32, also known as heme oxygenase I (HO-1), has received considerable attention, as it has been recently demonstrated that HO-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. This may open up new perspectives in medicine, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms, such as the heat shock response, through nutritional antioxidants, pharmacological compounds or gene transduction, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.     

Mitochondria, mitochondrial DNA and Alzheimer's disease. What comes first?

To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The mitochondria play central role in the bioenergetics of the cell and apoptotic cell death. In the past 20 years research has been directed at clarifying the involvement of mitochondria and defects in mitochondrial oxidative phosphorylation in late-onset neurodegenerative disorders, including AD. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of Abeta, which in a vicious cycle reinforces the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria in the cascade of events leading to AD, and we will try to provide an answer to the question "what comes first".     

Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids

Although oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative diseases such as Alzheimer's disease (AD), it is not fully understood how mitochondrial oxidative stress may induce neuronal death. We used mitochondrial transgenic neuronal cell cybrid models of sporadic AD (SAD) to investigate the effects of endogenously generated reactive oxygen species (ROS) on viability and cell death mechanisms. Compared to control (CTL) cybrids, SAD cybrids have increased accumulation of oxidative stress markers and increased apoptosis that is blocked by N-acetylcysteine (NAC) and zVAD.fmk. SAD cybrids also have increased basal activation of the MAPKs, Akt, and NF-kappa B. NF-kappa B activation and cybrid viability are enhanced by NAC. Inhibiting the activity of the PI3K pathway or NF-kappa B aggravates neuronal death. Exposure of CTL cybrids to H2O2 decreased viability and activated in a NAC-sensitive manner, the same intracellular signaling pathways active under basal conditions in SAD cybrids.     

Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment

Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system (CNS) for reasons that are not yet understood. Neurodegeneration is the umbrella term for the progressive death of nerve cells and loss of brain tissue. Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria. Widespread damage to mitochondria causes cells to die because they can no longer produce enough energy. Several lines of pathological and physiological evidence reveal that impaired mitochondrial function and dynamics play crucial roles in aging and pathogenesis of neurodegenerative diseases. As mitochondria are the major intracellular organelles that regulate both cell survival and death, they are highly considered as a potential target for pharmacological‐based therapies. The purpose of this review was to present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) and the importance of mitochondrial biogenesis as a potential novel therapeutic target for their treatment. Likewise, we highlight a concise overview of the key roles of mitochondrial electron transport chain (ETC.) complexes as well as mitochondrial biogenesis regulators regarding those diseases.     

Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer's disease

Alzheimer's disease(AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.     

Alzheimer's disease: cerebrovascular dysfunction, oxidative stress, and advanced clinical therapies

Many lines of independent research have provided convergent evidence regarding oxidative stress, cerebrovascular disease, dementia, and Alzheimer's disease (AD). Clinical studies spurred by these findings engage basic and clinical communities with tangible results regarding molecular targets and patient outcomes. Focusing on recent progress in characterizing age-related diseases specifically highlights oxidative stress and mechanisms for therapeutic action in AD. Oxidative stress has been investigated independently for its relationship with aging and cardiovascular and neurodegenerative diseases and provides evidence of shared pathophysiology across these conditions. The mechanisms by which oxidative stress impacts the cerebrovasculature and blood-brain barrier are of critical importance for evaluating antioxidant therapies. Clinical research has identified homocysteine as a relevant risk factor for AD and dementia; basic research into molecular mechanisms associated with homocysteine metabolism has revealed important findings. Oxidative stress has direct implications in the pathogenesis of age-related neurodegenerative diseases and careful scrutiny of oxidative stress in the CNS has therapeutic implications for future clinical trials. These mechanisms of dysfunction, acting independently or in concert, through oxidative stress may provide the research community with concise working concepts and promising new directions to yield new methods for evaluation and treatment of dementia and AD.     

Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy

Truncation of tau protein and oxidative stress have been implicated as important pathogenetic events in tauopathies including Alzheimer's disease (AD). We have generated a transgenic rat model that expresses a human truncated tau protein analogous to a variant form derived from sporadic AD. We employed this model to investigate the relationship between tau protein truncation and oxidative stress. We have found that rat cortical neurons (derived from transgenic animals) that had been cultured in vitro for 16 days showed an increased accumulation of reactive oxygen species (up to 1.4-fold increase; P < 0.01) when compared to neurons derived from nontransgenic control animals. Transgene-expressing neurons treated with inducers of oxidative stress, such as glucose oxidase (GO) and buthionine sulfoximine (BSO), displayed dramatically reduced survival (31.4 +/- 3.3 and 24.9 +/- 3.6%, respectively; both P < 0.001) compared to neurons from control animals (79.9 +/- 7.1%, survival following treatment with GO and to 98.2 +/- 3.8%, survival following treatment with BSO). The number of mitochondria in processes of neurons from transgenic animals was decreased by about one-third from that present in neurons from control animals. The results reveal that expression of a human truncated variant form of tau protein leads to the accumulation of reactive oxygen species and sensitizes rat cortical neurons to cell death induced by oxidative stress. This indicates that truncation of tau may precede oxidative stress in the pathogenesis of neurodegenerative diseases such as AD and other tauopathies. These findings may have implications for therapeutic strategies aiming at prevention of neurofibrillary degeneration and cognitive decline, and identify potential new targets for drug development.     

Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain

Oxidative damage on biological molecules has been proposed as a major cause of alterations observed in aging brain as well as in neurodegenerative diseases. In this study, we measured membrane fluidity in mitochondria extracted from three cerebral regions and cerebellum of Alzheimer disease (AD) patients and age-matched controls by means of fluorescence polarization technique. A significant reduction of mitochondrial membrane fluidity was found in AD, except in cerebellum. In controls, a decrease of membrane fluidity was observed along with age, and it was also related to the content of the oxidized nucleoside 8-hydroxy-2′-deoxyguanosine (OH⁸dG) in mitochondrial DNA (mtDNA). Alteration in membrane fluidity seems to be a result of lipid peroxidation, since it dramatically decreased when mitochondria were exposed to FeCl₂ and H₂O₂. The parallel increase of viscosity in mitochondrial membrane and the amount of OH⁸dG in mtDNA is suggestive of a relationship between these biological markers of oxidative stress. These results provide further evidence that oxidative stress may play a role in the pathogenesis of AD.     

Amyloid beta peptide, 4-hydroxynonenal and apoptosis

Considerable evidence suggests a role for oxidative stress in the pathogenesis of neuron degeneration in several neurodegenerative disorders including Alzheimer's disease (AD). Although debated, increasing evidence suggests that oxidative stress/damage (amyloid beta peptide, iron/hydrogen peroxide) or neurotoxic by-products of lipid peroxidation (4-hydroxy-2-nonenal, acrolein) lead to cell death through apoptosis or programmed cell death in AD. This review discusses current evidence supporting the role of oxidative stress/damage mediated apoptosis in in vitro models of neurodegeneration.     

Oxidative stress, mitochondrial damage and neurodegenerative diseases****

Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.     

Mitochondrial dysfunctions in neurodegenerative diseases:role in disease pathogenesis,strategies for analysis and therapeutic prospects

Fundamental organelles that occur in every cell type with the exception of mammal erythrocytes, the mitochondria are required for multiple pivotal processes that include the production of biological energy, the biosynthesis of reactive oxygen species, the control of calcium homeostasis, and the triggering of cell death. The disruption of anyone of these processes has been shown to impact strongly the function of all cells, but especially of neurons. In this review, we discuss the role of the mit...     

Brain biometals and Alzheimer's disease – boon or bane?

Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. A complicated array of molecular events has been implicated in the pathogenesis of AD. It is attributed to a variety of pathological conditions that share similar critical processes, such as oxidative stress, proteinaceous aggregations, mitochondrial dysfunctions and energy failure. There is increasing evidence suggesting that metal homeostasis is dysregulated in the pathology of AD. Biometals play an important role in the normal body functioning but AD may be mediated or triggered by disproportion of metal ions leading to changes in critical biological systems and initiating a cascade of events finally leading to neurodegeneration and cell death. The link is multifactorial, and although the source of the shift in oxidative homeostasis is still unclear, current evidence points to changes in the balance of redox transition metals, especially iron, copper (Cu) and other trace metals. Their levels in the brain are found to be elevated in AD. In other neurodegenerative disorders, Cu, zinc, aluminum and manganese are involved. This paper is a review of recent advances of the role of metals in the pathogenesis and pathophysiology of AD and related neurodegenerative diseases.     

Mitochondrial mechanisms of estrogen neuroprotection

Oxidative stress, bioenergetic failure and mitochondrial dysfunction are all implicated in the etiology of neurodegenerative diseases such as Alzheimer's disease (AD). The mitochondrial involvement in neurodegenerative diseases reflects the regulatory role mitochondrial failure plays in both necrotic cell death and apoptosis. The potent feminizing hormone, 17 β-estradiol (E2), is neuroprotective in a host of cell and animal models of stroke and neurodegenerative diseases. The discovery that 17-estradiol, an isomer of E2, is equally as neuroprotective as E2 yet is > 200-fold less active as a hormone, has permitted development of novel, more potent analogs where neuroprotection is independent of hormonal potency. Studies of structure–activity relationships and mitochondrial function have led to a mechanistic model in which these steroidal phenols intercalate into cell membranes where they block lipid peroxidation reactions, and are in turn recycled. Indeed, the parental estrogens and novel analogs stabilize mitochondria under Ca²⁺ loading otherwise sufficient to collapse membrane potential. The neuroprotective and mitoprotective potencies for a series of estrogen analogs are significantly correlated, suggesting that these compounds prevent cell death in large measure by maintaining functionally intact mitochondria. This therapeutic strategy is germane not only to sudden mitochondrial failure in acute circumstances, such as during a stroke or myocardial infarction, but also to gradual mitochondrial dysfunction associated with chronic degenerative disorders such as AD.     

Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer's disease

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction, increased oxidative stress and elevated apoptosis. Until now, AD cannot be diagnosed by a valid clinical method or a biomarker before the disease has progressed so far that dementia is present. Furthermore, no valid method is available to determine which patient with mild cognitive impairment (MCI) will progress to AD. Therefore, a correct diagnosis in the early stage of AD is not only of importance considering that early drug treatment is more effective but also that the psychological burden of the patients and relatives could be decreased. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and mitochondrial dysfunction as biomarker for AD in a peripheral cell model, the lymphocytes.