ENHANCED AMYLOIDOGENIC PROCESSING OF THE BETA-AMYLOID PRECURSOR PROTEIN IN GENE-TARGETED MICE BEARING THE SWEDISH FAMILIAL ALZHEIMERS-DISEASE MUTATIONS AND A HUMANIZED A-BETA SEQUENCE

The processing of the beta-amyloid precursor protein (APP) in vivo has been characterized in a novel animal model that recapitulates, in par t, the APP genotype of a familial form of Alzheimer's disease (AD). A gene-targeting strategy was used to introduce the Swedish familial AD mutations and convert mouse A beta to the human sequence. The mutant A PP is expressed at normal levels in brain, and cleavage at the mutant beta-secretase site is both accurate and enhanced. Furthermore, human A beta production is significantly increased to levels 9-fold greater than those in normal human brain while nonamyloidogenic processing is depressed. The results on A beta production extend similar findings ob tained in cell culture to the brain of an animal and substantiate A be ta as a etiological factor in Swedish familial AD. These animals provi de several distinguishing features over others created by conventional transgenic methodologies. The spatial and temporal expression pattern s of human A beta are expected to be faithfully reproduced because the gene encoding the mutant APP remains in its normal chromosomal contex t. Thus, the neuropathological consequences of human A beta overproduc tion can be evaluated longitudinally in the absence of potential mitig ating effects of APP overexpression or presence of the mouse A beta pe ptide.