Disturbance of the glutamatergic system in mice transgenic for the amyloidprecursor protein

Transgenic mice that overexpress human amyloid precursor protein (APP), eit her wild-type (APP/ wt) or the clinical APP/London (APP/Ld) mutant show dif ferential sensitivity towards glutamatergic drugs, i.e. a reduced response to N-methyl-D-aspartate (NMDA) and at the same time hypersensitivity for ka inic acid (KA). We have determined the distribution, number and the affinit y of KA and NMDA receptors in brain sections and homogenates. In hippocampa l and cortical membrane preparations, the affinity of MK-801 for the NMDA r eceptor was lower in APP/Ld mice compared to nontransgenic mice, while the number of binding sites was similar. Although expression of c-fos was induc ed following administration of NM DA, no consistent differences between tra nsgenic and nontransgenic mice were observed, suggesting an intact NMDA sig nal transduction pathway. No difference in either number or affinity of KA receptors was detected. The increased sensitivity to KA of the transgenic A PP/Ld mice was substantiated by correlating seizures and excitotoxic neuron al damage. Interestingly, transgenic mice that overexpress human wild-type APP showed intermediate sensitivity towards KA and NMDA compared to APP/Ld mice. These findings support the hypothesis that augmented levels of APP, e ven wild-type APP as in Down's syndrome, constitute a considerable burden o r stress for the brain. The results further support a key role for APP in d isturbing the glutamatergic system and thereby in the pathogenesis of Alzhe imer's disease.