Hyperglycemic but not normoglycemic global ischemia induces marked early intraneuronal expression of beta-amyloid precursor protein

Preischemic hyperglycemia is known to accentuate acute ischemic injury to n eurons, microglia, and endothelia. In the present study, we used a monoclon al antibody to the N-terminal portion of beta -APP to examine how the immun oreactivity of this: normal membrane glycoprotein is differentially influen ced by transient cerebral ischemia when carried out under normoglycemic vs. hyperglycemic conditions.. Anesthetized, physiologically regulated rats re ceived 12.5 min of global forebrain ischemia by bilateral carotid artery oc clusions plus systemic hypotension. Hyperglycemia was induced by intraperit oneal dextrose administration prior to ischemia. One or three days later, b rains were examined by beta -APP immunohistochemistry. Ischemia under hyper glycemic conditions led to the robust, widespread intraneuronal expression of beta -APP immunoreactivity in neocortex, hippocampus. thalamus, and stri atum of all 11 rats: this was most prominent at 24 h postischemia. Compared to rats with normoglycemic ischemia, numbers of beta -APP-immunopositive n eurons in the parietal cortex of hyperglycemic rots were increased by 5.9 f old at 24 h, and by 10.6 fold at 3 days postischemia. beta -APP-immunoposit ive neurons in hyperglycemic rats often exhibited striking morphological al terations typical of ischemic necrosis; however, no beta -APP immunoreactio n was observed in zones of frank infarction. Brains of normoglycemic rats ( n=11), by contrast, showed only weak beta -APP immunostaining in occasional non-necrotic pyramidal neurons of parietal neocortex, no necrosis was pres ent in thalamus. In sham-operated hyperglycemic rats, beta -APP immunostain ing of thalamic neurons was somewhat increased at 24 h. Western analysis re vealed that the hyperglycemia-induced intraneuronal overexpression of beta -APP was not associated with an overall increase in tissue levels. The resu lts of this study demonstrate that transient forebrain ischemia under hyper glycemic conditions leads to the early intraneuronal expression of beta -AP P within neuronal populations showing a heightened susceptibility to hyperg lycemia-induced accentuation of ischemic injury. Our data suggest that beta -APP or its metabolites may be involved in the injury process. (C) 2001 El sevier Science B.V. All rights reserved.