A mutant amyloid precursor protein (APP/RK) designed to interfere with processing by alpha-secretase caused a severe phenotype in transgenic mice, including behavioural abnormalities, i.e. neophobia, aggression, hypersensitivity to kainic acid, hyposensitivity to N-methyl-D-aspartate, and premature death [Moechars D. et al. (1996) Eur. molec. Biol. Org. J. 15, 1265-1274]. We now demonstrated that the APP/RK transgene did not disturb the expression of several other genes, i.e. endogenous amyloid precursor protein and amyloid precursor protein-like proteins, members of the low density lipoprotein receptor lipoprotein receptor family and several of their ligands, including apolipoprotein E, but expression of alpha-2-macroglobulin was never detected. Neither amyloid deposits nor neurofibrillary tangles were detected in the brain of APP/RK transgenic mice, even when 15-months-old. The tendency for seizures and hyposensitivity for N-methyl-D-aspartate was not due to or reflected in the distribution of the three major types of glutamate receptors. The major and consistent finding in transgenic APP/RK mice that died prematurely was extensive neurodegeneration and apoptosis, mainly in hippocampus and cortex, and accompanied by astrocytosis throughout the brain. Reduced synaptic density and dendritic damage was only observed in three transgenic mice that were killed shortly after positive observation of seizures. In addition, the distribution of cathepsin D and ubiquitin was abnormal in these mice.