Generation and Characterization of the First Murine Model of Alzheimer's Disease with Mutated APP Inserted in a BALB/c Background (C.B6/J-APP_swe)

Background: Numerous mouse models of Alzheimer's disease (AD) are available, but all suffer from certain limitations, thus prompting further attempts. To date, no one model exists with amyloidopathy in a BALB/c strain. Objective: To generate and characterize the C.B6/J-APP(swe) mouse, a model of AD with a mutated human gene for the amyloid-beta protein precursor (A beta PP) inserted in a BALB/c background. Methods: We analyzed five groups at different ages (3, 6, 9, 12, and 16-18 months) of C.B6/J-APP(swe) and wild-type mice (50% males and 50% females) for the main hallmarks of AD by western blotting, amyloid-beta (A beta) ELISA, immunocytochemistry, electrophysiology, and behavioral tests. Results: The C.B6/J-APP(swe) mouse displays early A beta PP and A beta production, late amyloid plaques formation, high level of Tau phosphorylation, synaptic deficits (reduced density and functional impairment due to a reduced post-synaptic responsiveness), neurodegeneration caused by apoptosis and necroptosis/necrosis, microgliosis, astrocytic abnormalities, and sex-related differences in explorative behavior, anxiety-like behavior, and spatial long-term and working memories. Social housing is feasible despite the intra-cage aggressiveness of male animals. Conclusion: C.B6/J-APP(swe) mice develop most of the distinctive features of AD and is a suitable model for the study of brain atrophy mechanisms and of the differences between males and females in the onset of cognitive/non-cognitive deficits.