Role of heme oxygenase-1 in the biogenesis of corpora amylacea.
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abstract
Corpora amylacea (CA) are glycoproteinaceous inclusions that accumulate in the human brain during normal aging and to a greater extent in Alzheimer's disease. We previously demonstrated that, in cultured rat astroglia, cysteamine (CSH) upregulates heme oxygenase-1 (HO-1) and promotes the transformation of normal mitochondria into CA-like inclusions. In the current study, primary cultures of neonatal rat astroglia were exposed to 880 micro M CSH for three months in the presence or absence of dexamethasone, a suppressor of HO-1 gene transcription. Cells were double-labeled with periodic acid-Schiff reagent (PAS) and antisera against ubiquitin, HO-1, or a mitochondrial epitope. CA were quantified and their immunostaining characteristics analyzed using confocal microscopy. HO-1 immunofluorescence was more abundant in cultures exposed to CSH alone relative to untreated control cultures and cultures exposed to both CSH and dexamethasone. Mature CA appeared as large (5-50 microM), spherical or polygonal, intensely PAS-positive inclusions within glial cytoplasm or deposited extracellularly. The inclusions manifested intense rim and, less commonly, homogeneous or stippled patterns of immunoreactivity for ubiquitin, HO-1, and the mitochondrial marker. Monolayers exposed to CSH exhibited 660% more CA relative to untreated controls (P < 0.05). Numbers of CA in cultures exposed to CSH were diminished by co-administration of 50 microg/ml dexamethasone (P < 0.05 relative to CSH alone) or 100 microg/ml dexamethasone (P < 0.05 relative to CSH alone). Numbers of CA in cultures co-treated with CSH and 50 microg/ml dexamethasone or 100 microg/ml dexamethasone were not significantly different from untreated control values. Up-regulation of HO-1 may contribute to the formation of CA in aging astroglia.
