A highly insoluble state of Aβ similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice

Amyloid-beta (A beta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited A beta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited A beta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic A beta was determined early on and did not gradually evolve with time. In tgAPP-AreSwe, A beta plaques displayed a patchy morphology with bundles of A beta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma A beta was observed following acute administration of an A beta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma A beta efflux. TgAPP-ArcSwe, with its insoluble state of deposited A beta, could serve as a complementary model to better predict the outcome of clinical trials. (C) 2007 Elsevier Inc. All fights reserved.