2 AMYLOID PRECURSOR PROTEIN TRANSGENIC MOUSE MODELS WITH ALZHEIMER DISEASE-LIKE PATHOLOGY

Mutations in the amyloid precursor protein (APP) gene cause early-onse t familial Alzheimer disease (AD) by affecting the formation of the am yloid beta (A beta) peptide, the major constituent of AD plaques, We e xpressed human APP(751) containing these mutations in the brains of tr ansgenic mice, Two transgenic mouse lines develop pathological feature s reminiscent of AD, The degree of pathology depends on expression lev els and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V71 7I mutation causes A beta deposition in neocortex and hippocampus of 1 8-month-old transgenic mice, The deposits are mostly of the diffuse ty pe; however, some congophilic plaques can be detected. In mice with 7- fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are C ongo Red-positive at first detection, These congophilic plaques are ac companied by neuritic changes and dystrophic cholinergic fibers, Furth ermore, inflammatory processes indicated by a massive glial reaction a re apparent, Most notably, plaques are immunoreactive for hyperphospho rylated tau, reminiscent of early tau pathology, The immunoreactivity is exclusively found in congophilic senile plaques of both lines, In t he higher expressing line, elevated tau phosphorylation can be demonst rated biochemically in 6-month-old animals and increases with age, The se mice resemble major features of AD pathology and suggest a central role of A beta in the pathogenesis of the disease.