Reactive oxygen its sources and significance in Alzheimer disease

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Emanuele    on Feb 07, 2010 Says :

very much informative. Thanks for the team.
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mariabougoulia,   favourited this   1 Years ago.
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Slide 1 : George Perry The University of Texas at San Antonio Xiongwei Zhu Case Western Reserve University Akihiko Nunomura The University of Yamanashi Paula Moreira The University of Coimbra Mark A. Smith Case Western Reserve University Reactive Oxygen: Its Sources and Significance in Alzheimer Disease
Slide 2 : Collaborators Case Western Reserve University Mark A. Smith Lawrence M. Sayre Kazuhiro Honda Robert P. Friedland Vernon Anderson Johns Hopkins University Takeda Chemical Company Keisuke Hirai Asahikawa Medical College Akihiko Nunomura Shigeru Chiba Alfred Rimm Quan Liu Grace Petot Luke Szweda University of South Alabama Miguel A. Pappolla University of California-San Diego Donald Cleveland Tohoku University School of Medicine Atsushi Takeda Thomas Jefferson University Hilary Koprowski University of Genova Massimo Tabaton Paul Carey Robert Petersen Gemma Casadesus Centro Biologia Molecular, Madrid Jesús Avila Donald Price Kyoto University School of Medicine Shun Shimohama Wataya Takafumi Michigan State University Rudy Castellani Universitat de Valencia Jose Viña Voyager Pharmaceutical Corporation Richard Bowen Patrick Smith Vincent Monnier University of Chile Ricardo Maccioni University of Texas at San Antonio Gjumrakch Aliev Paula I. Moreira University of Coimbra University of Wisconsin - Madison Craig Atwood
Slide 3 : Alzheimer disease attacks nerve cells in several regions of the brain. A. Cerebral Cortex: Involved in conscious thought and language. B. Basal forebrain: Has large numbers of neurons containing acetylcholine, a chemical important in memory and learning. C. Hippocampus: Essential to memory storage. The earliest signs of Alzheimer's are found in the nearby entorhinal cortex.
Slide 4 :
Slide 5 : Definition of oxidative stress Oxidative damage increases in Alzheimer disease Sources of reactive oxygen Responses to oxidative stress Involvement of pathological lesions Phosphorylation control of oxidative damage
Slide 6 : Definition of Oxidative Stress Classic definition: The production of reactive oxygen in excess of antioxidant mechanisms Evolving definition: Altered homeostatic balance resulting from oxidant insult.
Slide 7 : Normal Alzheimer Progression/Incidence Estrogen Acetylsalicylic acid (Aspirin) (-) Deprenyl (selegiline) Ibuprofen Dapsone Acetyl-L-Carnitine (ALCAR) Vitamin E Tenilsetam Diet Lipoic Acid Fruits and vegetables A leading hypothesis of the biological basis of aging is oxidative stress. Metabolism is the primary source of oxidants. AD is strictly age dependent Antioxidants are Protective
Slide 8 : Antioxidant Diet is Protective
Slide 9 : Oxidative damage increases in Alzheimer disease Control Alzheimer Lipid Peroxidation/Protein Adduction (4-HNE) Protein Oxidation (Free Carbonyl Groups) Nucleic Acids (8-OH-Guanosine) Alzheimer Alzheimer Control Control Alzheimer Control Glycoxidation (Carboxymethyllysine)
Slide 10 : Oxidative stress is an early event in AD. . . . . . . t Glycation Normal Neuron ? Pre-NFT I-NFT E-NFT 80HG Potential Mechanisms of Reactive Oxygen Species Generation in apparently normal neurons in Alzheimer Disease Active microglia Redox active metals Amyloid-b Advanced glycation endproducts Mitochondria ? ? Sources of reactive oxygen
Slide 11 : Potential mechanisms of reactive oxygen species generation in apparently normal neurons in Alzheimer Disease
Slide 12 : In situ hybridization of mtDNA Immunolocalization of Cytochrome oxidase 1 is increased in AD Alzheimer disease Control Mitochondrial components are increased in Alzheimer disease
Slide 13 : Examination of neurons in biopsy specimens shows normal mitochondria (A), mitochondria with broken cristae (B), and lipofuscin with vacuoles (C). * Mitochondria Percentage area of intact mitochondria is significantly decreased in cases of AD (n=8) as compared to age-matched controls (n=5). p=0.012 While mtDNA is increased, mitochondria are not.
Slide 14 : Mitochondria components are in autophagosomes
Slide 15 : Higher magnification shows both lipofuscin and associated vacuoles contain lipoic acid in cases of AD, arrowheads (C), but control cases lack this immunoreactivity (D). Scale bars = 0.25µm (A,C,D) and 0.5µm (B). Normal mitochondria accumulate LA (small gold particles, arrowheads) and COX-1 (large gold particles, arrows) (A). In addition to mitochondria (*) localization of LA (arrowheads) and COX-1 (arrows), electron-dense areas of lipofuscin contain lipoic acid, arrowheads (B). Lipoic acid localization: Post-embed staining method Lipoic Acid Cox-1 Lipoic Acid Cox-1 Lipoic Acid
Slide 16 : Microtubules are reduced specifically in pyramidal neurons. Numbers of microtubules decrease with normal aging Pyramidal neurons Non-pyramidal neurons p=0.000004 p=0.90 Microtubules (arrowheads) remain intact even in close proximity to paired helical filaments (*) PHF MT
Slide 17 : Could the mitochondrial problem be related to reduced axonal transport? O - 2 2 O 2 Fe H H mitochondria lysosome Alzheimer Disease Normal FeII 2
Slide 18 : Nucleic acid damage, as well as redox active metals are cytosolic 8-hydroxyguanosine Redox active metals
Slide :
Slide :
Slide 21 : Untreated Deferoxamine Fig.1 This cytoplasmic localization is decreased after chelation.
Slide 22 : Untreated RNase DNase Relative Density Iron (II) is increased in Alzheimer pyramidal neurons…. …and is similarly susceptible to RNase digestion.
Slide 23 : Ribosomal RNA has a significantly greater redox-active iron binding capacity than either transfer RNA or messenger RNA. 8OHG Formation
Slide 24 : Ribosomal RNA is 13 times more susceptible to oxidation than transfer RNA
Slide 25 : Ribosomal RNA is susceptible to cleavage by the Fenton reaction and simultaneously forms 8OHG
Slide 26 : Conformation plays a major role in this binding ability. After denaturation with formamide, the iron-binding capacity is dramatically reduced.
Slide 27 : Rabbit reticulocyte ribosome in vitro translation assay The Fenton reaction causes RNA cleavage … …with consequent decrease in protein synthesis.
Slide 28 : Purified ribosomes from Alzheimer hippocampus demonstrate significantly higher levels of metal dependent oxidation. Control AD Again, this metal dependent oxidation is susceptible to RNase digestion.
Slide 29 : Oxidized RNA, detected by 8OHG, is only present in ribosomes purified from Alzheimer disease Ribosomal RNA was immunoprecipitated with a monoclonal antibody against 8OHG and followed by RT-PCR using specific primers for human 28s and 18s rRNA fragments.
Slide 30 : What role do plaques and tangles play? In vitro
Slide :
Slide 32 : Oxidative damage (8OHG, blue) decreases with increased amyloid - b (brown) 17 yr. 61 yr. 31 yr. In vivo
Slide 33 : Levels of neuronal 8OHG in AD decrease with: A. increasing levels of amyloid (p=0.002 in cases with ApoE 4 and p=0.05 in cases lacking ApoE4) and B. the duration of the disease (p<0.03). AD with ApoE4 AD lacking ApoE 4 Control
Slide 34 : Levels of 8OHG immunoreactivity are significantly increased in familial AD cases (FAD ) cases (n=13, avg age 59 yr) compared with controls (n=15,avg age 66 yr). One presymptomatic case with PS-1 mutation shows a similar level to average FAD cases (A). In (FAD) there is a significant inverse correlation of Ab42 burden (B) but not with Ab 40 (C). Familial AD Cases
Slide 35 : t Accumulation is Associated with a Reduction in Oxidative Stress In AD cases, neurons containing NFT have lower levels of 8OHG than non-NFT bearing neurons in the same field.
Slide 36 : Are Amyloid-? and t Protective Responses Against a Cauldron of Oxidative Stressors in Alzheimer Disease?
Slide :
Slide 38 : Anti-HNE on immunoblots of total brain homogenate (AD and control) showing predominant labeling of NFH. NFH sequence contains multiple KSP domains. Antibody recognition of NFH and NFM (A) is abolished by HNE-lysine (B) but not cysteine (C) or histidine(D). Phosphorylation control of oxidative damage
Slide :
Slide 40 : Overexpressing NFH can protect neuronal cells from HNE toxicity (N2A mouse neuroblastoma cells) (M17 human neuroblastoma cells) * * * * * * HNE toxicity in N2A cells P=0.002 P=0.0007 P=0.01 P=0.025 P=0.004 P=0.029 HNE toxicity in M17 cells
Slide 41 : Summary Oxidative damage is a major feature of Alzheimer disease. The source of reactive oxygen likely involves metal directed oxidative modifications. Oxidative damage is met with increased antioxidant defenses. Many of the pathological changes of Alzheimer disease may be well-regulated antioxidant responses.

 


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