Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis

A mutant amyloid precursor protein (APP/RK) designed to interfere with proc essing by alpha-secretase caused a severe phenotype in transgenic mice, inc luding behavioural abnormalities, i.e. neophobia, aggression, hypersensitiv ity 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 expressio n of several other genes, i.e. endogenous amyloid precursor protein and amy loid precursor protein-like proteins, members of the low density lipoprotei n receptor lipoprotein receptor family and several of their ligands, includ ing apolipoprotein E, but expression of alpha-2-macroglobulin was never det ected. Neither amyloid deposits nor neurofibrillary tangles were detected i n the brain of APP/RK transgenic mice, even when 15-months-old. The tendenc y 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 rece ptors. The major and consistent finding in transgenic APP/RK mice that died premat urely was extensive neurodegeneration and apoptosis, mainly in hippocampus and cortex, and accompanied by astrocytosis throughout the brain. Reduced s ynaptic density and dendritic damage was only observed in three transgenic mice that were killed shortly after positive observation of seizures. In ad dition, the distribution of cathepsin D and ubiquitin was abnormal in these mice. (C) 1999 IBRO. Published by Elsevier Science Ltd.