Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum: An approach to understand pathological and biochemical alterations in AD

Sultana, Rukhsana; Boyd‐Kimball, Debra; Poon, H. Fai; Cai, Jian; Pierce, William M.; Klein, Jon B.; Merchant, Michael L.; Markesbery, William R.; Butterfield, D. Allan

doi:10.1016/j.neurobiolaging.2005.09.021

Cited by 306 publications

(322 citation statements)

References 86 publications

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“…Protein carbonyls, 3-NT and HNE levels are elevated in AD and MCI brains [3,4,[7][8][9][10][11][12]21,22]. HNE is a highly reactive product of arachidonic acid metabolism that is believed to interfere with normal cellular functions [3].…”

Section: Discussionmentioning

confidence: 99%

“…The reduced energy metabolism in AD may be due to oxidative dysfunction of some of the key metabolic or mitochondrial enzymes [7][8][9][10][11][12], which may lead to increased reactive oxygen species (ROS) production.…”

Section: Introductionmentioning

confidence: 99%

“…In AD brain ROS lead to protein oxidation [1,[7][8][9][10][11][12], lipid peroxidation [2,3], DNA and RNA oxidation [18][19][20], and neuronal dysfunction or death. Recent studies indicate that protein oxidation and lipid peroxidation in brain from mild cognitive impairment subjects [21,22], suggesting oxidative stress is an early event in the pathogenesis of AD.…”

Section: Introductionmentioning

confidence: 99%

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In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

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Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH), has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Aβ (1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro-and anti-apoptotic factor proteins. The present study was undertaken to test the hypothesis that i.p. injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitonially (i.p.) with D609 and subsequently treated in vitro with the oxidants Fe 2+ /H 2 O 2 (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals) and AD-relevant amyloid β-peptide 1-42 [Aβ (1-42)]. Brain mitochondria isolated from the gerbils previously injected i.p. with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3-NT), and cytochrome-c release compared to oxidant-treated brain mitochondria isolated from salineinjected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione-S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR) in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These anti-apoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

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“…All these proteins are involved directly or indirectly in the production of ATP in brains (74), and the oxidative modification of glycolytic enzymes likely leads to their inactivation. For example, CK, enolase, PGM1, GAPDH, and ATPase activities are reportedly diminished in AD brain (198,270,363). Glucose is the primary source of energy for the brain, which, though having a relatively small mass as a percentage of body mass, accounts for 20% of glucose metabolism and more than 30% of oxygen consumption.…”

Section: Identification Of Carbonylated Proteins In Brainmentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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“…Control subjects were without history of dementia or other neurological disorders and underwent annual mental status testing and semi-annual physical and neurological exams as part of the UK ADC normal volunteer longitudinal aging study, and had test scores in the normal range (Table II). Samples and demographics used for the AD study were described previously (Sultana et al, 2006). Additional demographic parameters of controls and subjects with MCI and AD without personal identifiers were made available by the UK ADC and are provided in Table I and Table II.…”

Section: Phospholipid Asymmetry Studiesmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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Redox proteomics identification of oxidized proteins in Alzheimer's disease hippocampus and cerebellum: An approach to understand pathological and biochemical alterations in AD

Cited by 306 publications

References 86 publications

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

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