Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer's Disease: linkage of poorer cognitive performance to tau pathology in forebrain

Abstract APPsw transgenic mice bearing the “Swedish” amyloid precursor protein (APP) mutation and JNPL3 transgenic mice bearing the P301L (Tau) mutation were compared to control non-transgenic (NT) mice in an extensive behavioral test battery administered between 5 and 8.5 months of age. APP mice were impaired in a variety of cognitive-based tasks prior to overt Aβ plaque development, making involvement of mutant APP overexpression and/or oligomeric Aβ assemblies most likely. Although Tau mice, as a group, were not impaired in any single behavioral measure, a collective assessment of behavioral measures through discriminant function analysis showed that Tau mice were impaired in overall behavioral (cognitive) performance. Moreover, correlation analyses involving Tau mice alone revealed linkage between poorer cognitive performance in all three water maze tasks and the number of neurofibrillary tangle (NFT)-containing neurons in neocortex and hippocampus. These findings indicate that: (1) APP mice show early and extensive cognitive impairment before evident Aβ deposition, and (2) the process or product of NFT formation in Tau mice is sufficient to deleteriously impact cognitive performance.