Poster Presentations P1 files by real-time reverse transcription-polymerase chain reaction is under way. Conclusions: The results of this study indicate the feasibility of oligo microarray-based gene expression profiling as a functional screening of compounds interfering with endoproteolysis of Notch and APP. CHF5022 appears to be a promising substrate-selective ␥-secretase modulator. P1-056 A␤ OVEREXPRESSION IS ASSOCIATED WITH ACCELERATION OF MOTOR IMPAIRMENT AND SUPEROXIDE DISMUTASE 1 AGGREGATION IN A MOUSE MODEL CO-EXPRESSING APP-C100 AND MUTANT SOD1 Qiao-Xin Li1,2, Su San Mok1,2, Katrina M. Laughton1,2, Catriona A. McLean3, Irene Volitakis1, Robert A. Cherny1, Anthony R. White1,2, Colin L. Masters1,2, 1Department of Pathology, The University of Melbourne, The Mental Health Research Institute of Victoria, Parkville, Australia; 2Centre for Neuroscience, The University of Melbourne, Parkville, Vic., Australia; 3Department of Anatomical Pathology, The Alfred Hospital, Prahran, Vic., Australia. Contact e-mail: qiao@unimelb.edu.au Background: Motor neuron disease (MND) is a neurodegenerative process affecting motor neurons in the spinal cord, brain stem and cortex which leads to progressive paralysis. The pathogenesis of MND remains unknown although familial cases exist where mutations are found in the superoxide dismutase (SOD1) gene suggesting a potential role for the SOD1 protein in sporadic cases. One of the major proposed mechanisms of motor neuron degeneration under investigation includes abnormal protein aggregation, in line with the known mechanism underlying other neurodegenerative disorders such as Alzheimer’s disease. The Abeta peptide, central to the molecular pathogenesis of Alzheimer’s disease, could also have a potential role in MND, as Abeta accumulation has been observed in brain and lumbar spinal cord of MND patients. Objective: We aim to investigate the potential role of Abeta in MND development. Methods: A double transgenic mouse line that overexpresses SOD1G93A and amyloid precursor protein (APP)-C100 was generated. TgC100 mice were used as they produce human Abeta at levels closer to the in vivo physiological Abeta concentration compared to other APP transgenic mice. Results: The transgenic mouse C100.SOD1G93A overexpresses Abeta and shows earlier onset of motor impairment but has the same life span as the single transgenic SOD1G93A mouse. To determine the mechanism associated with this early-onset phenotype, we measured copper and zinc levels in brain and spinal cord and found both significantly elevated in the single and double transgenic mice compared to non-transgenic mice. Increased glial fibrillary acidic protein and decreased APP levels in the spinal cord of C100.SOD1G93A mice compared to the SOD1G93A mice agree with the neuronal damage observed by immunohistochemical analysis. In the spinal cords of C100.SOD1G93A double transgenic mice, soluble Abeta was elevated in mice at end-stage disease compared to the pre-symptomatic stage. Buffer-insoluble SOD1 aggregates were significantly elevated in the presymptomatic mice of C100.SOD1G93A compared to the age-matched SOD1G93A mice, correlating with the earlier-onset of motor impairment in the C100.SOD1G93A mice. Conclusions: This study supports abnormal SOD1 protein aggregation as the pathogenic mechanism in MND and implicates a potential role for Abeta in the development of MND by exacerbating SOD1G93A aggregation. P1-057 PRESENILIN-1 I213T KNOCK-IN MUTATION ACCELERATES ALZHEIMER’S PHENOTYPE IN TG2576 MICE Kouhei Nishitomi1, Gaku Sakaguchi1, Yoshihiro Nakajima1, Motoko Hosono1, Chie Takeyama1, Takashi Kudo2, Masatoshi Takeda2, Akira Kato1, 1Pain & Neurology, Discovery Research Laboratories, Shionogi & Co., Ltd., Koka, Japan; 2Department of Psychiatry,Osaka University Graduate School of Medicine, Suita, Japan. Contact e-mail: kouhei.nishitomi@shionogi.co.jp S111 Background: Genetic causes of Alzheimer’s disease (AD) include mutations in the amyloid precursor protein (APP), presenilin-1 (PS1) and presenilin-2 (PS2). We previously generated a mouse line carrying a PS1 I213T targeted mutation. Mutant PS1 I213T knock-in (KI) mice have elevated levels of A␤42 in a gene-dosage-dependent manner. However, they have not deposited A␤ because of no humanized A␤ sequence. Therefore, the influence of PS1 I213T mutation on AD phenotype is not be investigated. Objective: We aimed to investigate the influence of targeted induction of PS1 bearing the familial AD mutation I213T on the aggravation of AD phenotype. Methods: We crossed heterozygous PS1I213T KI mice with Tg2576 mice expressing the Swedish mutation of APP (K670N and M671L) and studied A␤40 and A␤42 elevation, A␤ deposits and cognitive deficits using sandwich ELISAs, immunostaining with 4G8 and Y maze, respectively. Results: Heterozygous PS1I213T KI /Tg2576 mice showed a selective increase in A␤42 of their soluble fractions. In addition, PS1I213T KI mutation accelerated accumulation of not only A␤42 but also A␤40 in their insoluble fractions. These crossbreeds showed the eariler onset of A␤ deposition by 4 to 6 months compared to Tg2576 mice. Behavioral investigation shows that PS1I213T KI /Tg2576 mice showed a reduction of short-term memory in the Y maze at 3 to 4 months of age, before appearance of substantial A␤ deposition. Conclusions: These results indicate targeted induction of PS1 I213T mutation to Tg2576 mice increases the levels of brain A␤42, which is a potent pathogenic factor, and that the substantial elevation of A␤42 leads to pathological symptoms, the increase of insoluble A␤ and the formationn of A␤ plaques by aggreating with A␤40. PS1I213T KI /Tg2576 mice may be a useful animal model for studying the AD neuropathology and behavioral defect and for evaluation of therapeutic agents. P1-058 DIFFERENT EFFECTS OF L-(-)-NICOTINE ON BETA-AMYLOID PATHOLOGY IN THE BRAIN OF TWO TRANSGENIC MOUSE MODELS Monika M. Hedberg, Marie M. Svedberg, Tamanna Mustafiz, Christina Unger, Agneta Nordberg, Karolinska Institutet, Stockholm, Sweden. Contact e-mail: Monika.Hedberg@ki.se Background: Deposition of beta-amyloid (A␤) is an early and crucial event in the pathogenesis of Alzheimer s disease (AD). The anti-amyloid therapy is based upon lowering the A␤ load in the brain by affecting the production, aggregation or clearance of A␤, and thereby modifying disease progression. Recent studies in our research group have shown that both short- and long-term treatment with the natural enantiomer of nicotine, L-(-)-nicotine, dramatically reduce (up to 80%) the levels of both insoluble A␤1-40 and A␤1-42 in the brain of transgenic mice expressing the human gene APP695 harbouring the Swedish mutation (APPswe) (Nordberg et al 2002; Hellström-Lindahl et al 2002; Unger et al 2005). In the AD brain, acetylcholinesterase (AChE), is increased around A␤ plaques early in the process of A␤ deposition. It has been demonstrated that this increase may have a direct effect on plaque formation in the brain. Objective(s): To investigate the effect of L-(-)-nicotine on the neuropathology of double transgenic mice. Methods: To force A␤ pathology to appear earlier than in APPswe transgenic mice, which start to develop A␤ plaques at 9-12 months of age, we crossed APPswe transgenic mice with transgenic mice overexpressing human acetylcholinesterase (hAChE) resulting in double transgenic mice (hAChE-Tg//APPswe), which display diffuse pre-mature A␤ plaques at 7 months of age and compact mature A␤ plaques at 10 months of age. Both soluble and insoluble A␤ are already detectable at significant levels at 1 month of age (Svedberg et al submitted). hAChETg//APPswe transgenic mice and FVB/N//C57BL controls at 14 months of age were treated (s.c.) during 10 days with two daily injections of L-(-)nicotine (final concentration 0.45 mg/kg free base). Corresponding control groups received saline. Results: Opposite to the findings in APPswe transgenic mice, L-(-)-nicotine did not decrease the levels of insoluble A␤1-40 or A␤1-42 in the brain of the hAChE-Tg//APPswe transgenic mice. Conclusions: A plausible explanation is that the A␤ in the plaques is more tightly bound compared to in APPswe transgenic mice due to the