P1-072 TRANSGENIC MOUSE MODELS OF FAMILIAL BRITISH AND DANISH DEMENTIAS Janaky Coomaraswamy 1 , Martin C. Herzig 1 , Stephan A. Kaeser 1 , Jorge Ghiso 2 , Mathias Jucker 1 , 1 Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, Tuebingen, Germany; 2 Departments of Pathology and Psychiatry, New York University School of Medicine, New York, NY, USA. Contact e-mail: janaky.coomaraswamy@uni-tuebingen.de Background: The identification of the BRI2 gene, due to its relation to Familial British Dementia (FBD) and Familial Danish Dementia (FDD), has provided a new avenue to study the amyloid hypothesis, supporting the notion that the accumulation of amyloid is critical to the pathogenesis of neurodegenerative disease. Mutations of the BRI2 gene, a T-A transversion in FBD and ten nucleotide duplication in FDD, cause continued reading or a frame-shift at the stop codon resulting in BRI2 elongations. The proteo- lytic C-terminal fragments generated by normal processing of the elon- gated precursors accumulate in the form of vascular amyloid and hip- pocampal plaques, coinciding with tangles in both diseases. Objective: Since the identification of mutations in BRI2 causing FBD (1999) and FDD (2000) an animal model for either disease has remained elusive. Thus, it was our objective to create transgenic mice that recapitulate the pathogen- esis seen in patients. Methods: Mutations for FBD and FDD were created using point and insertional mutagenesis in cDNA encoding for the wild- type BRI2 protein. Transgenic mice were produced on a C57BL/6J back- ground expressing either transgene under the control of the SHaPrP pro- moter. Initial analyses have been perfomed on our Danish mice using histological and biochemical methods. Results: Initial results demonstrate that the Danish transgenic mice accumulate amyloid predominantly in the leptomeningeal vessels beginning as early as 2.5 months of age. This amyloid accumulation progresses further in the form of cerebral amyloid angiopathy (CAA) and parenchymal plaques as the mice age. Furthermore, the Danish amyloid deposition observed is immunoreactive with an anti- body specific for the C-terminal of the Danish protein as well as thioflavin S positive. Conclusions: This new transgenic mouse model of cerebral amyloidosis provides a new tool in the quest for a better understanding of the role of amyloid, particularly in CAA. This model may be beneficial not only to study mechanistic insights into FBD and FDD but also into the pathophysiology of Alzheimer’s disease and other aggregation proteopa- thies. P1-073 PROTEIN PROFILING OF THE HIPPOCAMPUS OF THE TG2576 TRANSGENIC AD MOUSE MODEL Bastiaan Hoogendoorn 1 , Darko Turic 1 , Ed Dudley 2 , Julia Grassl 2 , Richard Abraham 1 , Paul Hollingworth 1 , Valentina Moskvina 1 , Julie Williams 1 , Michael J. Owen 1 , Michael O’Donovan 1 , Lesley Jones 1 , 1 Cardiff University, Cardiff, United Kingdom; 2 University of Wales, Swansea, Swansea, United Kingdom. Contact e-mail: hoogendoornb@cardiff.ac.uk Background: While AD is at least in part a disease of abnormal APP processing, the sequential biochemical processes by which altered APP leads to disease remain unclear. Objective(s): Our aim is to identify proteins that are important in determining cellular changes in the progres- sion of AD. Methods: Using ProteinChip arrays, we are investigating protein changes in the hippocampus of the amyloid precursor protein (APP) transgenic mouse model (Tg2576) by examining protein profiles at different stages of disease progression. Results: We found 11 differentially regulated biomarkers in the hippocampus of 9 month old Tg2576 mice when compared with age-matched wild-type (WT) mice and were able to identify eight of these. Seven are mitochondrial component protein sub- units and, of these, five are from the oxidative phosphorylation complexes I, III and IV. Two subunits from complex I and one subunit from complex IV were up-regulated while one subunit from complex III and one from complex IV were down-regulated. Conclusions: This suggests a mitochon- drial energy involvement in the observed phenotype of these mice as has been observed previously in these mice and in human AD brain. We are currently assessing whether there is any genetic association of the genes relevant to these changes with susceptibility or progression of late-onset AD. P1-074 EATING & DRINKING IN AN APP HYPEREXPRESSION MODEL Ellen Vloeberghs 1 , Matthias Staufenbiel 2 , Debby Van Dam 1 , Peter P. De Deyn 1,3 , 1 Laboratory of Neurochemistry & Behaviour, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium; 2 Novartis, Institutes of BioMedical Research, Basel, Switzerland; 3 Department of Neurology - Memory Clinic, Middelheim General Hospital, Antwerp, Belgium. Contact e-mail: ellen.vloeberghs@ua.ac.be Background: To model Alzheimer dementia, transgenic mice overex- pressing the human amyloid precursor protein encoding the Swedish dou- ble mutation were generated. This APP23 model develops pathological features and models the demented patients’ learning and memory deficits. We have reported these transgenic mice to exhibit cage activity distur- bances, reminiscent of diurnal rhythm disturbances in Alzheimer patients, indicating as well the presence of neuropsychiatric symptoms of dementia. Objectives: With the aim of verifying whether the model also develops other behavioural problems, we assessed detailed eating and drinking patterns in heterozygous APP23 males of 3, 6 and 12 months of age. Furthermore, we longitudinally monitored body weight of a naive group of males starting at weaning. Methods: Eating and drinking behavior were simultaneously recorded by employing Skinner boxes during a 1-week recording period. The mouse cubicles are placed inside ventilated isolation compartments and equipped with a pellet feeder and an optical lickometer. The animals included in the growth curves were weighed twice a week until the age of 12 weeks, with subsequent monthly follow up. Results: We found heterozygous APP23 mice to take a higher number of food pellets and perform significantly more licking responses as well, in comparison with their wild-type littermates. From the age of 4.5 weeks onwards, heterozygous males weighed significantly less and this difference became even more outspoken with increasing age. Demented patients also exhibit weight loss and often dietary problems. Weight loss could induce second- ary metabolic alterations which might influence blood flow and cerebral function. Our results seem to support the hypothesis of the existence of a hypermetabolic state in Alzheimer patients. Conclusion: This is the first report, evidencing the existence of changes in eating and drinking behav- iour in an Alzheimer mouse model. APP23 mice become an even more promising and valuable animal model for Alzheimer’s disease-related research and opens perspectives for pharmacological and/or behavioural interventions. P1-075 CHOLINERGIC DYSFUNCTION, NEURONAL DAMAGE AND AXONAL LOSS IN TGCRND8 MICE Cristina Grossi 1 , Ilaria Luccarini 1 , Maria Cristina Rosi 1 , Arianna Bellucci 2 , Anna Fiorentini 1 , Fiorella Casamenti 1 , 1 University of Florence, Florence, Italy; 2 University of Brescia, Brescia, Italy. Contact e-mail: cristina.grossi@unifi.it Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized pathologically by the presence of senile plaques, neurofibril- lary tangles and marked neuronal death in the brain of affected patients. Cholinergic neurons originating in basal forebrain nuclei are the most vulnerable targets of degeneration in AD brain. Several lines of transgenic mice have been created to investigate the underlying neurodegenerative mechanisms in AD and to test new therapeutic approaches. Transgenic TgCRND8 mice (Chishti et al., 2001, J. Biol. Chem. 276, 21562) express- ing a double mutant form of amyloid precursor protein (APP) have been produced. S116 Poster Presentations P1