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

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

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

Estimated Average Daily Intake of Mercury from Environmental Sources

Metabolism and Transport of Elemental Mercury Vapor (Hg0)

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

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

Membrane Associated Targets of Mercuric Cation and Methylmercury

Partial List of Nucleotide Binding Proteins Inhibited by Hg2+

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

Many Nucleotide Binding Proteins Contain Cysteine Residues At Their Active Sites

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

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

Schematic of Nucleotide Photoaffinity Labeling

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

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

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

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

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

Biochemical Properties of Brain Tubulin

Structure of Neuronal Microtubules

Morphological Arrangement of the Neuronal Cytoskeleton

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

Disruption of Axonal Transport

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

Diagnosis of Alzheimer’s Disease

Pathological Hallmarks of AD

Proteins Associated with Senile Plaques

Possible Relationship Between Microtubule Disruption and Plaque and Tangle Formation

Genes Linked to Alzheimer’s Disease

Apolipoprotein E4 Genotype Increases the Susceptibility to the Development of AD

Apolipoprotein E (Apo E)

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

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

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

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

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

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

Illustration of Western Blotting

[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

Decreased [32P]8N3GTP--Tubulin Interactions in Hgo Vapor Exposed Rats Correlates with Elevated Brain Hg

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

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

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

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

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

Cytotoxicity of Endodontic Materials

Study Design

Table 2. Root-End Filling Materials Tested

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

Extraction and In Vitro Toxicity Testing of a Mercury Amalgam

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

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

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

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

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

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

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

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