Heme oxygenase-1 induction and mitochondrial iron sequestration in astroglia exposed to amyloid peptides

The mechanisms responsible for pathological iron deposition and mitochondri al insufficiency that have been documented in the brains of Alzheimer (AD) patients remain poorly understood. In the present study, we demonstrate tha t low-micromolar concentrations of amyloid(1-40) (A40) and amyloid(1-42) (A 42), 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 (FeCl3)-Fe-55 -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-trans ferrin served as the metal donor. We had previously shown that inhibitors o f HO-1 and the mitochondrial permeability transition pore (MTP) block the u ptake of mitochondrial iron in astrocytes exposed to the pro-oxidant effect s of dopamine and several pro-inflammatory cytokines. Similarly, in the cur rent study, amyloid-induced mitochondrial iron trapping was significantly a ttenuated by co-administration of the HO-1 transcriptional suppressor, dexa methasone (DEX) or the MTP blocker, cyclosporin A (CSA). Thus, the marked e nhancement of HO-1 expression previously demonstrated in AD-affected neuron s 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 rela ted mitochondrial iron deposition may be an important mechanism by which DE X protects tissues subjected to amyloid stress.