Molecular Mechanisms of Metal Toxicity and
Carcinogenicity
Environmental Health Perspectives 102,
Supplement 3, September 1994
Department of Biochemistry, University of Tennessee, Knoxville, Tennessee
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
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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