Journal
NEUROBIOLOGY OF AGING
Volume 30, Issue 9, Pages 1393-1405Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.11.022
Keywords
Immunotherapy; Solubility; ABeta-peptide; Alzheimer's disease; Amyloid beta; Transgenic
Categories
Funding
- Uppsala University
- Landstinget i Uppsala lan
- Swedish Brain Fund
- Bertil Hillstens Forskningsstiftelse
- Alzheimerfonden
- Sahlgrenska University Hospital
- Gamla Tjanarinnor
- Gun och Bertil Stolmes Stiftelse
- Magnus Bergvall
- Ahlonsstiftelsen
- Lars Hierta
- Lundstroms Minne
- Frimurarstiftelsen
- Svenska Lakarsallskapet
- Swedish Research Council [2006-2822, 2006-2818, 2006-6326, 2006-3464, 2004-2696]
- Knut and Alice Wallenberg foundation
- Swedish foundation for strategic research
- Sven and Ebba-Christina Hagbergs stiftelse
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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.
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