Heme oxygenase-1 induction and mitochondrial iron sequestration in astroglia exposed to amyloid peptides.
The mechanisms responsible for pathological iron deposition and mitochondrial insufficiency that have been documented in the brains of Alzheimer (AD) patients remain poorly understood. In the present study, we demonstrate that low-micromolar concentrations of amyloid1-40 (A40) and amyloid 1-42 (A42), peptides implicated in the pathogenesis of AD, increase levels of heme oxygenase-1 (HO-1) mRNA and protein in cultured rat astroglia. Furthermore, 6 days of exposure to amyloid augments the sequestration of 55FeCl3-derived iron by astroglial mitochondria without affecting the disposition of this metal in whole-cell and lysosomal compartments. Mitochondrial iron deposition was not observed in the amyloid-treated glia when diferric-transferrin served as the metal donor. We had previously shown that inhibitors of HO-1 and the mitochondrial permeability transition pore (MTP) block the uptake of mitochondrial iron in astrocytes exposed to the pro-oxidant effects of dopamine and several pro-inflammatory cytokines. Similarly, in the current study, amyloid-induced mitochondrial iron trapping was significantly attenuated by co-administration of the HO-1 transcriptional suppressor, dexamethasone (DEX) or the MTP blocker, cyclosporin A (CSA). Thus, the marked enhancement of HO-1 expression previously demonstrated in AD-affected neurons and astroglia may transduce amyloid (oxidative) stress into the abnormal patterns of iron deposition and mitochondrial insufficiency characteristic of this disease. Finally, in experiments employing cytotoxic concentrations of A40, we provide evidence that inhibition of HO-1 transcription and related mitochondrial iron deposition may be an important mechanism by which DEX protects tissues subjected to amyloid stress.
Ham
D
D
Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.
Schipper
H M
HM
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003603:Cytotoxins / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051547:Heme Oxygenase-1; D007473:Ion Channels; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D003603:Cytotoxins; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D007501:Iron; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1