that have been linked to relevant AD pathology. FDG-PET measurements may prove useful in the future evaluation of important pharmaceutical or lifestyle based intervention studies that target glucose control and AD risk in the older adult. POSTER PRESENTATIONS P4 P4-280 NAIVE AND PYROGLUTAMATED AMYLOID BETA ACCUMULATION IN THE MCGILL-R-THY1-APP RAT MODEL OF ALZHEIMER’S DISEASE Fabio Canneva 1 , Tiziana Melis 2 , Wanda Leon 3 , Florencia Iulita 3 , Julia Dobner 1 , Adriana Ducatenzeiler 3 , Stephan Schilling 4 , Stephan vonHoersten 1 , Claudio Cuello 3 , 1 University of Erlangen-N€ urnberg, Erlangen, Germany; 2 University of Cagliari, Cagliari, Italy; 3 McGill University, Montreal, Quebec, Canada; 4 Probiodrug AG, Halle, Germany. Background: According to the ’amyloidogenic hypothesis’, brain accumu- lation of amyloid-beta (Abeta) peptide species, which ultimately deposits into amyloid plaques, would be central and causative of the neuronal degen- eration and cognitive decline observed in patients affected by Alzheimer’s disease (AD). Interestingly, pre-fibrillar (i.e. pre-plaque), low-n oligomers (dimers, trimers) of Abeta have been found to inhibit long-term potentiation in normal rodent hippocampus as well as interfere with the retrieval of es- tablished memories. On the other hand, the highly insoluble pyrogluta- mate-Abeta (pE-Abeta), which results from N-terminal cleavage and subsequent enzymatic transformation of an exposed glutamate residue, is highly abundant in the brains of AD patients, and some recent studies sug- gest a correlation to their pathological stage. Methods: 13 month old McGill-R-Thy1-APP rats where behaviorally characterized by means of the Morris water maze and amyloid peptide accumulation in their brain in- vestigated by immunohistochemistry and ELISA using Abeta species-spe- cific antibodies. Results: Interestingly, the accumulation of the highly toxic Abeta1-42 over Abeta1-40 species measured in soluble brain extracts was found particularly abundant in homozygous rats as compared to hemizy- gous littermates (10-fold higher), positively correlating with their cognitive decline. On the other hand, comparable amounts of the two amyloid species were measured in the CSF of those animals, thus replicating what observed in human patients. Specific pE-Abeta immunoreactivity was found within am- yloid plaques deposited in the brain of homozygous animals. A further inves- tigation by ELISA confirmed a specific accumulation of the peptide within TBS-insoluble protein fractions from homozygous rats, whereas no signal was detectable from hemizygous or wt littermates. Conclusions: If on the one hand soluble (i.e. oligomeric) Abeta inversely correlates with the cog- nitive status of McGill-R-Thy1 tg rats, the highly insoluble pE-Abeta specif- ically accumulates in the brain of homozygous animals, where signs of an extended plaque pathology are detectable. Identifying the contribution of each of these two aspects to the amyloid pathology progression and the cog- nitive decline associated with AD will provide a better understanding for the development of new therapeutic strategies. P4-281 EARLY-LIFE IBUPROFEN TREATMENT PREVENTS AND REVERSES MEMORY DEFICITS WITHOUTALTERING BETA-AMYLOID PRODUCTION OR EPILEPTIFORM CORTICAL ACTIVITY IN THE APP-PS1 MODEL OF AD Damien Colas, Nathan Woodling, Bayara Chuluun, Grace Hagiwara, Prachi Priyam, Qian Wang, Craig H. Heller, Katrin Andreasson, Stanford University, Stanford, California, United States. Background: Epidemiological studies consistently report a reduced risk for AD among normal aging populations who chronically use non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Despite several stud- ies showing protective effects of NSAIDs in mouse models of AD, the mechanism of protection remains controversial, particularly with respect to the effects of NSAIDs on Amyloid-beta production and deposition. Be- yond A-beta pathology, memory deficits, hyperactivity, and aberrant corti- cal excitatory activity are hallmarks of mouse models of AD. In this study, we determined whether early-life ibuprofen treatment altered these phenotypes in the APPswe-PS1deltaE9 mouse model of AD. Methods: APP-PS1 mice develop deficits in novel object recognition (NOR) begin- ning at 4 months, an age at which the first amyloid plaques begin to accu- mulate. Mice were thus treated with ibuprofen from 3mo (prevention trial) or from 4mo (reversal trial). At 5-6mo, the mice were tested using NOR and open field tests for behavioral analysis. EEG recordings from pa- rietal cortex were used to determine the effects on cortical epileptiform ac- tivity (spiking). In a parallel cohort of mice treated from 3mo to 6mo, brains were isolated and samples analyzed by western blot, ELISA, Congo Red staining, and 6E10 immunohistochemistry to analyze A-beta production and deposition. Results: In both the prevention and reversal trials, ibuprofen completely rescued NOR performances to wild-type levels. However, this rescue was not associated with any alteration in locomotor hyperactivity or aberrant epileptiform EEG patterns. Furthermore, ibuprofen had no effect on A-beta deposition as assessed by Congo Red or 6E10 analysis. By west- ern blot and ELISA analysis, we additionally found no change in soluble A-beta levels or APP processing by beta- or alpha-secretase. Conclusions: Our study highlights for the first time a dissociation between cognitive per- formance, A-beta levels, and aberrant cortical epileptiform activity in AD model mice. Our data also offer novel insights to the effects of NSAID treat- ment during pre-plaque stages. Specifically, these findings demonstrate that memory performance can be rescued at early stages without affecting aber- rant EEG spiking activity which are thought accordingly to be linked to A- beta in these models. Our findings additionally support future investigations into the protective effects of NSAIDs independent of A-beta production. P4-282 NEURONAL CORRELATES UNDERLYING THE ESTABLISHMENT OF BRAIN COGNITIVE RESERVE IN A MOUSE MODEL OF ALZHEIMER’S DISEASE Alice Krezymon 1 , Laure Verret 2 , Helene Halley 3 , J-M Lassalle 3 , Bernard Frances 3 , Claire Rampon 3 , 1 CNRS, Toulouse, France; 2 Gladstone Institut of Neurological Disease, San Francisco, California, United States; 3 CRCA, Toulouse, France. Background: Environmental factors have been suggested to impact the risk and development of Alzheimer’s disease (AD). The "cognitive reserve" hypothesis proposes protective effects of complex experiences, such as sus- tained cognitive engagement and leisure activities, against dementia. Thus, cognitive stimulations during mid-life might induce long-lasting modifica- tions of the brain, making it more resilient against dementia and Developing Topics e9