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

Philipson, Ola; Hammarström, Per; Nilsson, K. Peter R.; Portelius, Erik; Olofsson, Tommie; Ingelsson, Martin; Hyman, Bradley T.; Blennow, Kaj; Lannfelt, Lars; Kalimo, Hannu; Nilsson, Lars N.G.

doi:10.1016/j.neurobiolaging.2007.11.022

« Previous Next »Neurobiology of Aging
Volume 30, Issue 9 , Pages 1393-1405, September 2009

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

Ola Philipson
- Department of Public Health and Caring Science, Uppsala University, SE-751 85 Uppsala, Sweden
Per Hammarström
- Department of Chemistry, IFM, Linköping University, SE-581 83 Linköping, Sweden
K. Peter R. Nilsson
- Department of Chemistry, IFM, Linköping University, SE-581 83 Linköping, Sweden
- UniversitätsSpital Zürich, Institute of Neuropathology, CH-809 Zürich, Switzerland
Erik Portelius
- Department of Neuroscience and Physiology, Sahlgrenska University Hospital, SE-431 80 Mölndal, Sweden
Tommie Olofsson
- Department of Genetics and Pathology, Uppsala University, University Hospital, SE-751 85 Uppsala, Sweden
Martin Ingelsson
- Department of Public Health and Caring Science, Uppsala University, SE-751 85 Uppsala, Sweden
Bradley T. Hyman
- Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA
Kaj Blennow
- Department of Neuroscience and Physiology, Sahlgrenska University Hospital, SE-431 80 Mölndal, Sweden
Lars Lannfelt
- Department of Public Health and Caring Science, Uppsala University, SE-751 85 Uppsala, Sweden
Hannu Kalimo
- Department of Genetics and Pathology, Uppsala University, University Hospital, SE-751 85 Uppsala, Sweden
- Department of Pathology, Helsinki University, University Hospital of Helsinki, FI-00014 Helsinki, Finland
Lars N.G. Nilsson
- Department of Public Health and Caring Science, Uppsala University, SE-751 85 Uppsala, Sweden
- Corresponding author at: Public Health and Caring Science/Geriatrics, Rudbeck Laboratory, Dag Hammarskjölds Väg 20, SE-751 85 Uppsala, Sweden. Tel.: +46 18 471 5039; fax: +46 18 471 4808.

Received 16 August 2007; received in revised form 5 October 2007; accepted 19 November 2007. published online 15 January 2008.

Abstract

Amyloid-β (Aβ) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Aβ 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 Aβ 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 Aβ was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Aβ plaques displayed a patchy morphology with bundles of Aβ 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 Aβ was observed following acute administration of an Aβ antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Aβ efflux. TgAPP-ArcSwe, with its insoluble state of deposited Aβ, could serve as a complementary model to better predict the outcome of clinical trials.

Keywords: Immunotherapy, Solubility, ABeta-peptide, Alzheimer's disease, Amyloid beta, Transgenic