Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APP SWE Alena V. Savonenko, a,b,c Guilian M. Xu, b Donald L. Price, b,c,d David R. Borchelt, b,c, * and Alicja L. Markowska a,1, * a Department of Psychology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA b Department of Pathology, Johns Hopkins School of Medicine, 720 Rutland Avenue, 558 Ross Building, Baltimore, MD 21205, USA c Department of Neuroscience, Johns Hopkins School of Medicine, 720 Rutland Avenue, 558 Ross Building, Baltimore, MD 21205, USA d Department of Neurology, Johns Hopkins School of Medicine, 720 Rutland Avenue, 558 Ross Building, Baltimore, MD 21205, USA Received 27 February 2002; revised 24 September 2002; accepted 25 October 2002 Abstract Amyloid deposition appears to be an early and crucial event in Alzheimer’s disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of -amyloid (A), neuritic plaques, and glial responses. In studies of cognition in these animals, there have been several reports of memory disturbances well before the appearance of amyloid deposits. We have developed two distinct lines of transgenic mice (C3-3 and E1-2) that express the “Swedish” variant of APP (APP SWE ) at levels that are approximately three-fold higher than endogenous mouse APP. Both lines have been backcrossed to C57BL/6J mice for 10 generations. Here, we use longitudinal and cross-sectional studies to evaluate the cognitive performance of our animals, where the concentration of A1-42 in brain increases with aging from low levels (2–10 pmol/g) at 6 –14 months of age to relatively high levels (60 –100 pmol/g) at 24 –26 months, when deposits of A were beginning to form. When 12-month-old mice were tested in tasks that assess reference and working memory, transgenic mice from both lines could not be distinguished from nontransgenic littermates. Further study of 24- to 26-month-old transgenic mice (C3-3 line) found no evidence of memory impairment despite the presence of high levels of human A (60 –100 pmol/g). Thus, the expression of APP SWE at approximately three-fold over endogenous levels, which is sufficient to induce amyloid deposition at advanced ages, does not significantly erode cognitive performance in aged mice. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Place discrimination; Water maze; Longitudinal; Cross-sectional; Memory; -Amyloid; Aging Introduction Amyloid deposition appears to be an early and crucial event in Alzheimer’s disease (AD) (Borchelt et al., 1997; Morris, 1996; Selkoe, 1994). To generate animal models of amyloidogenesis and amyloid-associated abnormalities, mice expressing full-length amyloid precursor protein (APP) with mutations linked to familial AD (FAD) have been created; these animals exhibit abnormalities character- istic of AD including A amyloid deposits, neuritic plaques, and glial responses (Dewachter et al., 2000; Games et al., 1995; Hsiao et al., 1996; Janus et al., 2000; Wyss-Coray et al., 1997). The relationships between memory function in mice and APP expression, A secretion, and A deposition have been examined in multiple studies, yielding mixed outcomes. For example, mice expressing mutant APP via the PDGF promoter show impaired spatial memory well before the deposition of A (Dodart et al., 1999, 2000; Hsia * Corresponding authors. Alicja L. Markowska, National Institutes on Aging, Bethesda, MD 20892. David R. Borchelt, Department of Pathology, Johns Hopkins School of Medicine, Ross Building, Room 558, 720 Rut- land Avenue, Baltimore, MD 21205. Fax: +1-410-955-9777. E-mail addresses: markowsa@nia.nih.gov (A.L. Markowska); drbor@jhmi.edu (D.R. Borchelt). 1 Current address: SRO, National Institutes on Aging, Bethesda, MD 20892. R Available online at www.sciencedirect.com Neurobiology of Disease 12 (2003) 194 –211 www.elsevier.com/locate/ynbdi 0969-9961/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0969-9961(02)00012-8