MUTANT AND NATIVE HUMAN BETA-AMYLOID PRECURSOR PROTEINS IN TRANSGENICMOUSE-BRAIN

Human beta-amyloid precursor protein (beta APP) has been targeted to t ransgenic neurons using synapsin I promoter-based chimeric transgenes. Native human beta APP was introduced as well as beta APP containing m utations genetically linked to familial Alzheimer's disease (AD) and t o hereditary cerebral hemorrhage with amyloidosis-Dutch type. In mouse brain, human beta APP RNA was up to 60% as abundant as total endogeno us beta APP RNA. Human beta APP gene expression was most abundant in t he CA subfields of the hippocampus and in the piriform cortex. Correct processing of human beta APP at the beta-secretase cleavage site was demonstrated in transgenic mouse brains. Despite a 40% increase in tot al beta APP immunoreactivity in lines expressing mutant human beta APP , no evidence of amyloid deposition was found in brains of mice up to 14 months in age. Higher levels of mutant human beta APP, increased ag e, or other factors may be necessary to elicit beta-amyloid-related ne uropathologies in the rodent brain.