The long term goal of this research project is to understand iron regulation in the nervous system and how perturbations in iron metabolism may have a role in neurodegenerative disorders. However, although this research program is currently focusing on iron, the absence of the word """"""""iron"""""""" in the title of this application is deliberate. Because transferrin, the iron mobilization protein, and ferritin, the iron storage protein, are known to bind a number of cations in addition to iron, the ultimate goal of this research project may lie in understanding metal regulation in the brain. The first metal in addition to iron that we have chosen to examine is aluminum because of the potential through controversial role of aluminum in Alzheimer's disease. The objectives of this proposal are: (i) to demonstrate the cell types(s) which contain transferrin, the transferrin receptor, and/or ferritin in the normal human CNS; (ii) to determine the protein and mRNA levels of the major components of the iron system in different brain regions; (iii) to determine alterations in the distribution and concentration of the major iron components (both protein and mRNA in Alzheimer's and Parkinson's diseases; (iv) to determine if areas of high ferritin and transferrin receptor density coincide with high levels of aluminum in Alzheimer's brain tissue; (v) to demonstrate that aluminum complexed to transferrin will compete efficiently with transferrin-iron for the transferrin receptor in the brain and in vitro; (vi) to determine the ability of transferrin-aluminum (relative to transferrin-iron) to regulate transferrin and ferritin synthesis in culture; (vii) to determine if a sialovariant form of transferrin exists in a higher ratio than normal in brain, CSF or plasma in Alzheimer's or Parkinson's Disease. The potential significance of this latter objective lies in the possibility of a biological marker for Alzheimer's or Parkinson's Disease. The technical approaches utilized in this proposal include immunohistochemistry, immunoassay, immunoblots, northern blots, and receptor binding. The results of the studies in this proposal will immediately contribute to helping understand the number of neurological disorders thought to be associated with a disruption in iron metabolism. The potential for transferrin and ferritin to modulate a number of metals may lead to new areas of investigation in the neurosciences.
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