HYPERSENSITIVITY TO SEIZURES IN BETA-AMYLOID PRECURSOR PROTEIN-DEFICIENT MICE

Secreted forms of the beta-amyloid precursor protein (beta-APP) have n europrotective properties in vitro and may be involved in the containm ent of neuronal excitation. To test whether loss of secreted forms of beta-APP (sAPPs) may enhance excitotoxic responses, we injected mice h omozygous for a targeted mutation of the beta-APP gene (beta-APP(Delta /Delta)) intraperitoneally with kainic acid. We found that in these mi ce, kainic acid induced seizures initiated earlier, and acute mortalit y was enhanced compared to isogenic wild-type mice independently from the callosal agenesis phenotype observed to occur at increased frequen cy in APP mutant mice, Expression of c-fos in cortex and cingulate gyr us was enhanced in beta-APP(Delta/Delta) mice, although the amount of structural damage and apoptosis in the hippocampal pyramidal cell laye r and cortex was similar to that of controls. When cerebellar granule cell cultures and cortical neuronal cultures were challenged with glut amate receptor agonists, the rates of cell death and apoptosis of beta -APP(Delta/Delta) mice were indistinguishable from those of controls. Therefore, deficiency of sAPPs causes facilitation of seizure activity in the absence of enhanced cell death. Since enhanced seizures were o bserved also in mice homozygous for a deletion of the entire beta-APP gene, this phenotype results from a loss of APP rather than from a dom inant effect of APP(Delta).