Metallochemistry of Neurodegeneration

I: Introduction;

1:General model for protein misfolding, aggregation, amyloid formation and neurodegeneration;

2: Specificity of molecular mechanisms in major neurodegenerative diseases;

Alzheimer disease (AD);

Parkinson Disease;

Amyotrophic lateral sclerosis;

Prions diseases;

3: Models of amyloid seeding in neurodegenerative diseases;

References;

II: Blood- Brain Barrier and roots of entry of metal ions into the brain. Metal transport and distribution in the brain;

1: General features of blood-brain barrier;

2: Iron and aluminium;

3: Manganese;

4: Lead and mercury;

5: The olfactory pathway of metal entry into the brain;

6: Astroglia and metal accumulation;

References;

III: Metal ion induced redox reactions, oxidative stress and possible impact on Neurodegeneration;

1: Metal induced production of ROS;

2: Nitric oxide;

3: Oxidative stress and aging;

4: ROS, protein oxidation and aberrant protein interactions;

5: Peroxidation of lipids in aging brain;

6: Impact of oxidative stress on DNA;

7: ROS and cell death;

References;

IV: Copper Metabolism in the Brain;

1: Introduction;

2: Models of Copper Metabolism;

3: Mammalian Copper Homeostasis;

4: Mammalian Cellular Copper Metabolism;

5: Neurodegenerative diseases and Copper;

6: Wilson and Menkes Diseases;

7: Familial Amyotrophic Lateral Sclerosis (FALS);

8: Conclusions;

References;

V: Lithium, a neuroprotective element;

IMPase;

GSK-3;

References;

VI: Neurotoxicity of aluminium;

1: Neurochemistry of Aluminum;

2: Aluminum and the etiology of Alzheimer's Disease (AD);

References;

VII: Manganese in the brain functioning;

1: Introduction;

2: Manganese Absorption;

3: Manganese Transport to the Brain;

4: Manganese Uptake in the Brain;

5: Proteins that Utilise Manganese;

6: Manganese Neurotoxicity;

7: Effects on Brain Function;

8: Neurological Disease related to Manganese;

9 : Conclusions ;

References;

VIII: Alzheimer's disease: which metal now?;

1: Amyloid Precursor Protein;

2: Cleavage of APP and formation of ?-Amyloid;

3: Neurofibrillary Tangles;

4: Copper, APP and A?;

5: Metals and Alzheimer's Disease;

6: A balance between copper and zinc;

7: The rise of iron;

8: Any more metals in Alzheimer's disease;

9: Coordination chemistry of metal ions interacting with APP;

References;

IX: Prion diseases and and redox active metal;

1: Introduction;

2: Cu binding to PrPc;

3: Details of copper(II) co-ordination to mammalian PrPC and its fragments;

Binding of Cu(II) ion by a single octapeptide repeat Pro-His-Gly-Gly-Gly-Trp-Gly-Gln;

pH-dependence of Cu2+ binding to octapeptide fragment;

Binding of Cu2+ ions to dimeric and tetrameric octapeptide fragments;

4: The Fifth and Sixth Binding Sites Located in N-Terminal Domain;

5: Binding of Cu(II) and other metals to PrP91-126 region;

Cu(II) coordination to PrP106-126 (KTNMKHMAGAAAAGAVVGGLG);

Involvement of His-96 in the interaction of Cu(II) with the neurotoxic peptide fragment;

The comparison of the binding abilities of octameric and neurotoxic regions towards Cu2+ ions;

6: Cu2+ coordination to chicken PrP;

7: Copper Mediated PrP Internalisation;

8: Copper Transport;

9: PrP as an Antioxidant;

10: Manganese Binding;

11: Cell Death and Metals;

12: Metal Changes in TSEs;

13: Copper and Mutant Prions;

14: Conclusions;

References;

X: Are Metals Involved in Cu-Zn Superoxide Dismutase Related Familial Amyotrophic Lateral Sclerosis;

References;

XI: Parkinson disease: any role for metals;

1: Introduction;

2: Cell Death in Parkinson's Disease;

3: Genetics of Parkison's Disease;

4: The Proteins Associated with Parkinson's Disease;

Parkin;

?-Synuclein;

5: Metals in Parkinson's Disease;

6: Bioinorganic chemistry in Parkinson disease;

Binding of copper ions to ?-synuclein and its fragments;

7: Metal ions and catecholamines;

8: The neuromelanin of substantia nigra and metal ions;

9: Conclusions;

References;

XII: Chelating Agents in Metal Neurotoxicity;

Copper;

Lead;

Mercury;

Iron;

References;

XIII: Metal Complexes in the Brain Imaging and Diagnosis;

Gadolinium compounds;

Monocrystalline Iron Oxide Nanocompounds;

Delivery of MRI Contrast Agents;

MRI staining of the hippocampal system;

Contrast Agents in Stem Cells Therapy;

Thallium Autometallography;

Targeting of Contrast Agents to Alzheimer's disease Amyloid Plaques;

References