The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice

The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (A beta) sequence and leads to Alzheimer's disease (AD). Arctic A beta peptides more easily form A beta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APP(ArcSwe)) and transgenic mice with the Swedish mutation alone (tg-APP(Swe)). Intense intraneuronal A beta-immunoreactive staining was present in young tg-APP(ArcSwe) mice, but not in tg-APP(Swe) mice. Intracellular A beta aggregates in tg-APP(ArcSwe) were strongly stained by antibodies recognizing the N-terminus of A beta, while those recognizing the C-terminus of A beta stained weakly. The A beta aggregates inside neurons increased with age and predated extracellular A beta deposition in both tg-APP(ArcSwe) and tg-APP(Swe) mice. Senile plaque deposition was markedly accelerated in tg-APP(ArcSwe) mice, as compared to tg-APP(Swe) mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular A beta aggregates in association with a rapid onset of senile plaque deposition. (C) 2005 Elsevier Inc. All rights reserved.