Expression of heme oxygenase-1 in the senescent and Alzheimer-diseased brain.

Heme oxygenase-1 is a cellular stress protein expressed in brain and other tissues in response to oxidative challenge and other noxious stimuli. Using immunohistochemistry and immunofluorescent labeling in conjunction with laser scanning confocal microscopy, we observed intense immunoreactivity of heme oxygenase-1 in neurons of the hippocampus and temporal cortex of Alzheimer-diseased (AD) brain relative to age-matched control specimens. Furthermore, we demonstrated consistent colocalization of heme oxygenase-1 to glial fibrillary acidic protein-positive astrocytes, neurofibrillary tangles, and senile plaques in the AD specimens. In AD hippocampus, approximately 86% of glial fibrillary acidic protein-positive astrocytes expressed heme oxygenase-1, whereas only 6.8% of hippocampal astrocytes in normal senescent control specimens were immunopositive for heme oxygenase-1 (p < 0.0001). In regions other than the hippocampus and neocortex, such as the substantia nigra, the proportion of astrocytes expressing heme oxygenase-1 in the experimental group (12.8%) was not significantly different from that in the controls (6.4%, p > 0.05). Robust 32-kd bands corresponding to heme oxygenase-1 were observed by Western blotting of protein extracts derived from AD temporal cortex and hippocampus after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Heme oxygenase-1 bands were very faint or absent in protein extracts prepared from control specimens. These results indicate that heme oxygenase-1 is significantly overexpressed in neurons and astrocytes of AD hippocampus and cerebral cortex relative to control brains. Upregulation of heme oxygenase-1 in AD brain supports the contention that the affected tissues are experiencing chronic oxidative stress. In addition, the excessive generation of carbon monoxide, a metabolite of heme degradation, may participate in the pathogenesis of AD.