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 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.
Sahlas
D J
DJ
Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada H3T 1E2.
Liberman
A
A
Schipper
H M
HM
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D003543:Cysteamine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D002479:Inclusion Bodies; D010503:Periodic Acid-Schiff Reaction; D051381:Rats
D003543:Cysteamine; D003907:Dexamethasone; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1