Neurobiology of Aging 30 (2009) 1393–1405 A highly insoluble state of A similar to that of Alzheimer’s disease brain is found in Arctic APP transgenic mice Ola Philipson a , Per Hammarstr ¨ om b , K. Peter R. Nilsson b,c , Erik Portelius d , Tommie Olofsson e , Martin Ingelsson a , Bradley T. Hyman f , Kaj Blennow d , Lars Lannfelt a , Hannu Kalimo e,g , Lars N.G. Nilsson a,∗ a Department of Public Health and Caring Science, Uppsala University, SE-751 85 Uppsala, Sweden b Department of Chemistry, IFM, Link¨ oping University, SE-581 83 Link¨ oping, Sweden c Universit¨ atsSpital Z ¨ urich, Institute of Neuropathology, CH-809 Z¨ urich, Switzerland d Department of Neuroscience and Physiology, Sahlgrenska University Hospital, SE-431 80 M ¨ olndal, Sweden e Department of Genetics and Pathology, Uppsala University, University Hospital, SE-751 85 Uppsala, Sweden f Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129, USA g Department of Pathology, Helsinki University, University Hospital of Helsinki, FI-00014 Helsinki, Finland Received 16 August 2007; received in revised form 5 October 2007; accepted 19 November 2007 Available online 14 January 2008 Abstract Amyloid- (A) is a major drug target in Alzheimer’s disease. Here, we demonstrate that deposited A 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 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 was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, A plaques displayed a patchy morphology with bundles of A 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 was observed following acute administration of an A antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma A efflux. TgAPP-ArcSwe, with its insoluble state of deposited A, could serve as a complementary model to better predict the outcome of clinical trials. © 2007 Elsevier Inc. All rights reserved. Keywords: Immunotherapy; Solubility; ABeta-peptide; Alzheimer’s disease; Amyloid beta; Transgenic 1. Introduction Alzheimer’s disease (AD) is, according to the amyloid cas- cade hypothesis, initiated by aggregates of amyloid- (A) peptides which directly or indirectly cause neurodegenera- tion and multiple cognitive deficits. The strongest support for ∗ Corresponding author at: Public Health and Caring Science/Geriatrics, Rudbeck Laboratory, Dag Hammarskj¨ olds V¨ ag 20, SE-751 85 Uppsala, Sweden. Tel.: +46 18 471 5039; fax: +46 18 471 4808. E-mail address: lars.nilsson@pubcare.uu.se (L.N.G. Nilsson). this theory comes from genetic discoveries of mutations in the β-amyloid precursor protein (APP) and presenilin genes that are linked to early onset AD. These mutations favor pro- duction of -amyloid peptide 42 (A42) and its deposition in the brain parenchyma (Hardy and Selkoe, 2002). Great efforts are devoted to develop drugs that clear A aggre- gates or reduce A production, e.g., by immunotherapy or by targeting regulatory enzymatic pathways. APP transgenic mice allow such disease-modifying strategies to be tested in vivo before being launched in clinical trials (Games et al., 1995; Hsiao et al., 1996). Surprisingly, a great variety of 0197-4580/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2007.11.022