P3-014: longitudinal characterization of cvn mouse for alzheimer's disease using behavioral, imaging, and biomarker end-points

CVN mouse, with APPSweDI mutations and crossed with NOS2 knockout line, exhibits wide range of AD hallmarks including increased insoluble Aβ and plaque formation, inflammation, tau phosphorylation, hippocampal neuronal death and behavioral deficits. Validation data from Charles River CVN mouse in-house testing colony shows reproducible AD defects, and positions CVN mouse as one of the most complete rodent AD model available. Wild-type and CVN mice were studied at 3, 6, 9 and 12 months of age. Behavioral testing battery included various tests including o pen field, Barnes maze, r adial arm water maze and c ontextual fear conditioning. Fine motor deficits were studied by using Motorater kinematic analysis system. At each age point, MRI and MRS evaluation was performed before tissue, CSF and plasma collection for analysis. Immunohistochemical stainings for amyloid plaques and inflammatory cells and biochemical analysis of soluble and insoluble amyloid were performed. Significant behavioral deficits were seen at the age of 6 months in c ontextual fear conditioning and later in Barnes maze and in r adial arm water maze. Robust pathological changes, including increased number of dense amyloid plaques in hippocampus, thalamus and cortex, were evident. Significant inflammatory response was detect ed as microgli osis and CD45-positi ve cells heavily condensed around the plaques in all brain regions studied. MRS showed significant AD-related changes in brain metabolites starting at 9 months of age. The CVN mouse model provides several desired AD-related end points and hence a more complete tool to study novel therapies targeted for treatment of AD.