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Oxidative Stress and Inflammation in Neurodegenerative Diseases George Perry and Mark A. Smith Case Western Reserve University Cleveland, Ohio

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I. Alzheimer’s Disease Background © TND 2004

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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

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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.

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Brain Inflammation in Alzheimer’s Disease

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A leading hypothesis of the biological basis of aging is oxidative stress. The prevalence of AD is strictly age-dependent

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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 ADTauist 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

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II. Oxidative Stress Role in AD

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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

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Causes of Reactive Oxygen Species Generation in Alzheimer’s Disease Active microglia Redox active metals Amyloid-b Advanced glycation endproducts Mitochondria

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Partial reduction of oxygen generates ROS

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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

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III. Mitochondrial and microtubule abnormalities are found in Alzheimer’s Disease.

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Mitochondrial DNA is increased in Alzheimer’s pyramidal neurons. * * * * Deleted Wild type Alzheimer Control mtDNA In situ hybridization of mtDNA

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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.

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Mitochondria components are in autophagosomes.

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Normal Alzheimer Could the mitochondrial problem be related to microtubules?

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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

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Microtubules (arrowheads) remain intact even in close proximity to paired helical filaments (*).

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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

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Increased amyloid - b (brown) correlates with decreased oxidative damage (8OHG, blue). Down Syndrome 17 yr. 61 yr. 31 yr.

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How do lesions protect? Oxidatively damaged Metal binding sites Reduce oxidative stress

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Is amyloid- protective against a cauldron of oxidative stressors in Alzheimer’s Disease? Are there signs of established antioxidant responses in AD?

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V. Phosphorylation of Cytoskeletal Proteins Drives Oxidative Modifications.

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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.

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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).

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VI. Therapeutics

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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

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VII. Summary

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Primary etiology Cellular response Oxidative stress and inflammation Ab and t AD phenotype Current therapeutic targets

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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

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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.