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Toxic Effects of Mercury on Central Nervous System Nucleotide Binding Proteins: Potential Role in Alzheimer’s Disease


1/25/99

 Click here to start

Table of Contents

  1. Toxic Effects of Mercury on Central Nervous System Nucleotide Binding Proteins: Potential Role in Alzheimer’s Disease

  2. I. Sources and Fate of Absorbed Elemental Mercury Vapor (Hg0)

  3. Estimated Average Daily Intake of Mercury from Environmental Sources

  4. Metabolism and Transport of Elemental Mercury Vapor (Hg0)

  5. Oxidation of Elemental Mercury Vapor (Hg0) by the Enzyme Catalase

  6. Oxidation of Mercury Vapor in the Brain and Trapping of Hg2+ by Binding to Brain Proteins

  7. Membrane Associated Targets of Mercuric Cation and Methylmercury

  8. Partial List of Nucleotide Binding Proteins Inhibited by Hg2+

  9. II. Toxic Effects of Mercury on Brain Nucleotide Binding Proteins (NBPs)

  10. Many Nucleotide Binding Proteins Contain Cysteine Residues At Their Active Sites

  11. These Active Site Cysteine Sulfhydryl (-SH) Groups Are Critical for Proper Enzyme Function

  12. Mercury Can Covalently Bind to Active Site Sulfhydryls (-SH) and Inhibit Enzyme Activity

  13. Schematic of Nucleotide Photoaffinity Labeling

  14. Inhibitory Effects of Mercury on a Mixture of Nucleotide Binding Proteins can be Detected and Quantified by Photoaffinity Labeling

  15. Neuronal Tubulin, the Most Abundant Brain Protein, Is Especially Vulnerable to Mercury

  16. Reported Effects of Mercury and Other Sulfhydryl Reactive Heavy Metals on the In Vitro Polymerization of Purified Brain Tubulin

  17. Reported Effects of Mercury and Other Sulfhydryl Reactive Heavy Metals on Microtubules (MTs) in Cell Culture

  18. Photoaffinity Labeling With [32P]8N3GTP Has Been Used Extensively to Study Tubulin Biochemistry

  19. Biochemical Properties of Brain Tubulin

  20. Structure of Neuronal Microtubules

  21. Morphological Arrangement of the Neuronal Cytoskeleton

  22. Microtubules Form the Structural Framework for Axonal Transport - A Process Essential for the Survival of Neurons

  23. Disruption of Axonal Transport

  24. III. Possible Role of Mercury and Sulfhydryl Reactive Heavy Metals in the Etiology of Alzheimer’s Disease (AD)

  25. Diagnosis of Alzheimer’s Disease

  26. Pathological Hallmarks of AD

  27. Proteins Associated with Senile Plaques

  28. Possible Relationship Between Microtubule Disruption and Plaque and Tangle Formation

  29. Genes Linked to Alzheimer’s Disease

  30. Apolipoprotein E4 Genotype Increases the Susceptibility to the Development of AD

  31. Apolipoprotein E (Apo E)

  32. Substitution of Arginine for Cysteine in Apo E3 and Apo E4 at Positions 112 and 158 Results in Loss of Potential Binding Sites for Sulfhydryl Reactive Heavy Metals such as Mercury

  33. Mercury is Significantly Elevated in the Brains of Alzheimer’s Disease Subjects Relative to Controls

  34. Hg2+ Induces Aberrant [32P]8N3GTP-b-Tubulin Interactions Indicative of Alzheimer’s Disease

  35. SDS-PAGE Separation of Control and AD Brain Hippocampus Homogenates After Photolabeling with [32P]8N3GTP

  36. Autoradiogram of the Photolabeled Control & AD Brain Hippocampus Homogenates Showing Decreased [32P]8N3GTP-b-Tubulin Interactions

  37. Western Blotting of the Hippocampus Homogenates with Anti-b-Tubulin Antibodies Shows the Amount of b-Tubulin Protein is Not Reduced in the AD Brain Relative to Controls Despite a Significant Decrease in Photolabeling

  38. Illustration of Western Blotting

  39. [32P]8N3GTP-b-Tubulin Interactions are Aberrant in Both the Hippocampus and Frontal Pole of the Majority of AD Brain Homogenates Despite Normal Levels of Total b-Tubulin

  40. Decreased [32P]8N3GTP-b-Tubulin Interactions in Hg0 Vapor Exposed Rats Correlates with Elevated Brain Hg

  41. Decreased [32P]8N3GTP-b-Tubulin Interactions in Hg0 Vapor Exposed Rats Correlates with Elevated Brain Hg

  42. Decreased [32P]8N3GTP-b-Tubulin Interactions in Hg0 Exposed Rats & AD Brain Homogenates is Not Due to Decreased Levels of b-Tubulin Protein

  43. Treatment of Human Control Brain Homogenate with Sulfhydryl Reactive Heavy Metals Results in a Concentration Dependent Decrease [32P]8N3GTP Photolabeling of b-Tubulin

  44. EDTA Prevents Cd, Cu & Zn But Potentiates Hg Inhibition of [32P]8N3GTP Photolabeling of Brain b-Tubulin

  45. Partial List of Studies Demonstrating the Cytotoxic Effects of Mercury Containing Amalgams

  46. Cytotoxicity of Endodontic Materials

  47. Study Design

  48. Table 2. Root-End Filling Materials Tested

  49. Osorio et al., (1998). J. Endodon. 24,91-96.

  50. Extraction and In Vitro Toxicity Testing of a Mercury Amalgam

  51. Sequential Extracts of a Mercury Containing Amalgam Significantly Inhibit [32P]8N3GTP Interactions with b-Tubulin in Human Control Brain Homogenate

  52. Inhibition of [32P]8N3GTP Photolabeling of Brain b-Tubulin Was Greater Than 65% for All Amalgam Extracts Tested While the 45 kDa Protein Band was Not Significantly Effected

  53. Sequential Extracts of a Mercury Containing Amalgam Inhibit [32P]N3ATP Interactions with Purified ATP Binding Enzymes

  54. The Extract of a Mercury Containing Amalgam Inhibits [32P]N3ATP Interactions with Purified ATP Binding Enzymes

  55. Phosphorylase a (Phos a) Catalyzes the Sequential Removal of Glycosyl Residues from Glycogen

  56. Phosphoglycerate Kinase (PGK) and Pyruvate Kinase (PK) Function in the Breakdown of Glucose to Pyruvate in Glycolysis and in the Substrate Level Production of ATP

  57. Creatine Kinase (CK) and Adenylate Kinase (AK) Maintain ATP Levels in Tissues With High, Fluctuating Energy Demands Such as Brain and Muscle

Author: J. Curt Pendergrass Ph.D.
              President, ALT, Inc., Assistant Director, TEST Foundation

 

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