| Iron and Aluminum Homeostasis in Neural Disorders Environ Health Perspect Key words: aluminum, iron, ferritin, proteases, plaque formation, Alzheimer's disease
This paper was presented at the Second International Meeting on Molecular Mechanisms of Metal Toxicity and Carcinogenicity held 10-17 January 1993 in Madonna di Campiglio, Italy.
We are grateful to the Council for Tobacco Research and PMERF, Knoxville, TN for financial support.
Address correspondence to Dr. Jayant G. Joshi, Department of Biochemistry, University of Tennessee, Knoxville, TN 37996-0840. Telephone (615) 974-5148. Fax (615) 974-6306.
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The brain is the most compartmentalized organ. It is also highly aerobic. Because nerve cells grow but do not regenerate, the brain is the organ best suited for the accumulation of metabolic errors colocalized in specific areas of the brain over an extended period. Alzheimer's disease (AD) is primarily a neurological disorder of the elderly. It is suggested that this disorder results from the accumulation of such errors, and that AD onset aluminum and iron contribute to but do not necessarily initiate the onset of the disease. In vitro and in vivo evidence summarized here suggests that this is effected by interfering in the utilization of glucose and glucose-6-phosphate, and sequestration of iron by ferritin. ß-amyloid precursor proteins (ß-APPs) are normal components of the human brain and some other tissues. Proteolysis of these, presumably by serine proteases, generates a 39 to 42 amino acid long peptide, the  -amyloid (ß-AP) . In AD brains, ß-AP aggregates into plaque, the hallmark of AD brains. Some of the -APPs also contain a 56 amino acid long segment which inhibits serine proteases. We show that in vitro, at pH 6.5, aluminum activates ß-chymotrypsin 2-fold and makes it dramatically resistant to protease inhibitors such as bovine pancreatic trypsin inhibitor (bPTI) or its mimic present in the ß-amyloid precursor proteins (ß-APPs) . Iron and oxygen are reported to favor cross-linking of ß-AP in vitro. Because iron and ferritin are components of neurotic plaques, and acidic pH are reported in AD brains, we suggest that deregulation of iron and aluminum homeostasis permit their colocalization, and contribute to the accumulation of metabolic errors leading to neuronal disorders including the formation of AD (senile) plaques. -- Environ Health Perspect 102(Suppl 3) :207-213 (1994) Key words: aluminum, iron, ferritin, proteases, plaque formation, Alzheimer's disease
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