perry Oxstress

Information about perry Oxstress

Published on March 6, 2008

Author: Samuel

Source: authorstream.com

Content

Slide1:  Oxidative Stress and Inflammation in Neurodegenerative Diseases George Perry and Mark A. Smith Case Western Reserve University Cleveland, Ohio Slide2:  I. Alzheimer’s Disease Background © TND 2004 Slide3:  Alzheimer’s Disease 4 million Americans have Alzheimer’s Disease; by 2050, 14 million will have AD.1 AD is one of the top 10 leading causes of death in Americans over 65 years of age.2 AD is the third most costly disease after heart disease and cancer.1 Federal funding for AD is 4 to 7 times lower than for heart disease, cancer or AIDS.1 Slide4:  PET (positron emission tomography) scans show differences in brain activity between a normal brain and a brain affected by Alzheimer’s disease. Blue and black in the images above denote inactive areas. Normal Alzheimer Metabolism is the primary source of oxidants. Slide5:  Brain Inflammation in Alzheimer’s Disease Slide7:  A leading hypothesis of the biological basis of aging is oxidative stress. The prevalence of AD is strictly age-dependent Slide8:  Proposed Chronology of Changes in AD Tauist and BAPtist Amyloid-b Deposition [Senile Plaque] Tau Phosphorylation [Neurofibrillary Tangles] Neuronal death/Dysfunction: Dementia Tau Phosphorylation [Neurofibrillary Tangles] Amyloid-b Deposition [Senile Plaque] Proposed Chronology of Changes in AD Tauist and BAPtist:  Proposed Chronology of Changes in AD Tauist and BAPtist Amyloid-b Deposition [Senile Plaque] Tau Phosphorylation [Neurofibrillary tangles] Neuronal death: Dementia Tau phosphorylation [Neurofibrillary tangles] Amyloid-b deposition [Senile plaque] Causes Consequences Slide10:  II. Oxidative Stress Role in AD Slide11:  Oxidative Stress Classic definition: The production of reactive oxygen in excess of antioxidant mechanisms Modern definition: Altered homeostatic balance resulting from oxidant insult. Oxidative Modifications Affect All Cellular Macromolecules:  Oxidative Modifications Affect All Cellular Macromolecules 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) Is oxidative stress an early event in AD? In the proposed sequence of degenerative events, it occurs earlier than cytoskeletal alterations.:  Is oxidative stress an early event in AD? In the proposed sequence of degenerative events, it occurs earlier than cytoskeletal alterations. ? . . . . . . t Glycation Normal Neuron ? Pre-NFT I-NFT E-NFT 80HG Slide14:  Causes of Reactive Oxygen Species Generation in Alzheimer’s Disease Active microglia Redox active metals Amyloid-b Advanced glycation endproducts Mitochondria Slide15:  Partial reduction of oxygen generates ROS Slide16:  Consequences Superoxide dismutase NSAIDS confer protection Complement pathway activation Microglial activation and association with amyloid plaques Heme-oxygenase- 1 induction Induction of “adaptive” gene responses and repair enzymes Apoptosis pathway Slide17:  III. Mitochondrial and microtubule abnormalities are found in Alzheimer’s Disease. Slide18:  Mitochondrial DNA is increased in Alzheimer’s pyramidal neurons. * * * * Deleted Wild type Alzheimer Control mtDNA In situ hybridization of mtDNA Slide19:  mtDNA 8OHG Nitrotyrosine The distribution of increased neuronal levels of mtDNA (A), 8OHG (B) and nitrotryosine (C) in Alzheimer’s Disease completely overlaps. The same neurons in adjacent serial sections are numbered. Slide20:  Mitochondria components are in autophagosomes. Slide21:  Normal Alzheimer Could the mitochondrial problem be related to microtubules? Slide22:  Study of biopsy samples shows microtubules are reduced specifically in AD pyramidal neurons. Pyramidal neurons Non-pyramidal neurons p=0.000004 p=0.90 Numbers of microtubules decrease with normal aging Microtubule Density Microtubule Density Microtubule Length Control AD -PHF AD +PHF Control AD -PHF AD +PHF Slide23:  Microtubules (arrowheads) remain intact even in close proximity to paired helical filaments (*). Slide24:  IV. Interplay of pathological lesions and oxidative stress t Accumulation is Associated with a Reduction in Oxidative Stress:  t Accumulation is Associated with a Reduction in Oxidative Stress t/80HG t Slide27:  Increased amyloid - b (brown) correlates with decreased oxidative damage (8OHG, blue). Down Syndrome 17 yr. 61 yr. 31 yr. Slide28:  How do lesions protect? Oxidatively damaged Metal binding sites Reduce oxidative stress Slide29:  Is amyloid- protective against a cauldron of oxidative stressors in Alzheimer’s Disease? Are there signs of established antioxidant responses in AD? Slide30:  V. Phosphorylation of Cytoskeletal Proteins Drives Oxidative Modifications. Slide31:  p-ERK p-JNK/SAPK p-p38 Stress response kinases are induced tau assembly induced by HNE is dependent on phosphorylation Effect of HNE on tau assembly. Phospho-tau polymers following 1mM HNE. Slide32:  In vitro modification of NFH and NFM by HNE is dependent upon lysine residues… Levels of HNE do not accumulate with age in the mouse’s sciatic nerve …and phosphorylation state. Antibody recognition of NFH and NFM (A) is abolished by HNE-lysine (B) but not cyteine (C) or histidine(D). Slide33:  VI. Therapeutics Slide34:  Progression/Incidence Estrogen Acetylsalicylic acid (Aspirin) (-) Deprenyl (selegiline) Ibuprofen Dapsone Acetyl-L-Carnitine (ALCAR) Vitamin E Tenilsetam Antioxidants and anti-inflammatories are protective Diet Lipoic Acid Fruits and vegetables Antioxidant diet is protective:  Antioxidant diet is protective Slide36:  VII. Summary Slide37:  Primary etiology Cellular response Oxidative stress and inflammation Ab and t AD phenotype Current therapeutic targets Slide38:  Mitochondria Nitric Oxide Mutated genes (SOD, bPP, asynuclein) Phospholipid metabolism Proteolysis Redox Active Metals Advanced Glycation Endproducts Microglia Proteins Lipids Nucleic Acid Apoptosis Alzheimer Disease Parkinson Disease ALS Stroke Multiple Sclerosis Vitamin E Lipoic Acid Metal Chelation Slide39:  Conclusions Metal catalyzed oxidative damage to all categories of macromolecules is increased. Antioxidant pathways and inflammatory responses are induced. “Pathological changes” may be compensations that are critical to maintaining oxidative homeostasis.

Related presentations


Other presentations created by Samuel

Explorer Pizarro
28. 02. 2008
0 views

Explorer Pizarro

Holy Qurbana
07. 04. 2008
0 views

Holy Qurbana

Overture OME Conf
27. 03. 2008
0 views

Overture OME Conf

Elizabethanol
21. 03. 2008
0 views

Elizabethanol

wsmo tutorial
18. 03. 2008
0 views

wsmo tutorial

A1Schengen
14. 03. 2008
0 views

A1Schengen

11174695641Carlo Dade
12. 03. 2008
0 views

11174695641Carlo Dade

Ashtongrcae
11. 03. 2008
0 views

Ashtongrcae

seedcount presentation 003
04. 10. 2007
0 views

seedcount presentation 003

5 WATER CYCLE
06. 12. 2007
0 views

5 WATER CYCLE

AW9
07. 12. 2007
0 views

AW9

metadata and documentation
10. 12. 2007
0 views

metadata and documentation

nav5
07. 11. 2007
0 views

nav5

Idioms
16. 11. 2007
0 views

Idioms

CrsVR5
20. 11. 2007
0 views

CrsVR5

ch5
01. 01. 2008
0 views

ch5

hamamatsu
03. 01. 2008
0 views

hamamatsu

Rohan Shah Anti Dumping Issues
04. 01. 2008
0 views

Rohan Shah Anti Dumping Issues

aquaculture impacts
04. 01. 2008
0 views

aquaculture impacts

class09a
13. 11. 2007
0 views

class09a

artotSuB
19. 11. 2007
0 views

artotSuB

Ken Turbitt BMC Software
06. 11. 2007
0 views

Ken Turbitt BMC Software

radtrans07
14. 11. 2007
0 views

radtrans07

enzyme cofactors
04. 03. 2008
0 views

enzyme cofactors

35347
26. 02. 2008
0 views

35347

200701 PCC Bridges
29. 12. 2007
0 views

200701 PCC Bridges

xrtod comissioning diagnostics
09. 11. 2007
0 views

xrtod comissioning diagnostics

imageSlideshow
03. 10. 2007
0 views

imageSlideshow

fuchsia brands farm
29. 12. 2007
0 views

fuchsia brands farm

PozziSmall2002 Istanbul
28. 09. 2007
0 views

PozziSmall2002 Istanbul

climate cop11 emilio sempris
23. 11. 2007
0 views

climate cop11 emilio sempris