Role of heme oxygenase-1 in the biogenesis of corpora amylacea

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 to880 µM CSH for three months in the presence or absence of dexamethasone, a suppressor ofHO-1 gene transcription. Cells were double-labeled with periodic acid-Schiffreagent (PAS) and antisera against ubiquitin,HO-1, or a mitochondrial epitope. CA were quantified and their immunostaining characteristics analyzed using confocalmicroscopy.HO-1 immunofluore scence 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 µM), spherical orpolygonal, 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 µg/ml dexamethasone (P < 0.05 relative to CSH alone)or 100 µg/ml dexamethasone (P < 0.05relative to CSH alone). Numbers of CA incultures co-treated with CSH and 50 µg/mldexamethasone or 100 µg/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.