Journal
EXPERIMENTAL GERONTOLOGY
Volume 35, Issue 6-7, Pages 821-830Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0531-5565(00)00148-0
Keywords
aging; Alzheimer disease; amyloid; astrocyte; dopamine; heme oxygenase-1; iron; mitochondria; oxidative stress; Parkinson disease
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The mechanisms responsible for excessive iron deposition and mitochondrial insufficiency in the aging and degenerating nervous system remain poorly understood. Heme oxygenase-1 (HO-1) is a 32 kDa stress protein that degrades heme to biliverdin, free iron and carbon monoxide. Our laboratory has shown that cysteamine, dopamine, beta -amyloid, IL-1 beta and TNF-alpha up-regulate HO-1 followed by mitochondrial sequestration of non-transferrin-derived Fe-55 in cultured rat astroglia. In these cells and in rat astroglia transfected with the human HO-1 gene, mitochondrial iron trapping is abrogated by the HO-1 inhibitors, tin-mesoporphyrin and dexamethasone. We determined that HO-1 immunoreactivity is enhanced greatly in neurons and astrocytes of the hippocampus and cerebral cortex of Alzheimer subjects and co-localizes to senile plaques and neurofibrillary tangles (NFT). HO-1 staining is also augmented in astrocytes and decorates neuronal Lewy bodies in the Parkinson nigra. Collectively, our findings suggest that HO-1 over-expression contributes to the pathological iron deposition and mitochondrial damage documented in these aging-related neurodegenerative disorders. We recently observed that, paradoxically, HO-1 mRNA levels are markedly suppressed in peripheral lymphocytes of patients with early sporadic Alzheimer disease and may thus provide a useful biological marker of this condition. (C) 2000 Elsevier Science Inc. All rights reserved.
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