Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3×TgAD and 2×TgAD mice

Keywords: C99 Ab 2ÂTgAD 3ÂTgAD Alzheimer's disease Behavior Actimetry Morris water maze a b s t r a c t The triple transgenic mouse model (3ÂTgAD: APPswe, Tau P301L , PS1 M146V) recapitulates both amyloid b (Ab)-and tau-related lesions as well as synaptic and memory deficits. In these mice, we reported an early apathy-like behavior and alterations in synaptic plasticity appearing concomitantly with intraneuronal accumulation of C99 in the subiculum. To delineate the genuine contribution of C99 on the above phenotypes, we generated double transgenic mice (2ÂTgAD: APPswe, Tau P301L) that accumulate C99 without Ab deposition or hyperphosphorylation of tau and compared them to 3ÂTgAD mice. Here, we show that both TgAD mice display similar decreases in long-term potentiation and in spontaneous lo-comotor activity measured by actimetry suggesting that the synaptic alterations and the apathy-like behavior were likely linked to C99 rather than Ab. However, spatial learning alterations, assessed by the Morris water maze task, are more pronounced in 3ÂTgAD than in 2ÂTgAD, suggesting that both Ab and C99 contribute to defects in the acquisition of spatial information. Finally, even if similar results are observed in males, cognitive and non-cognitive deficits are more severe in females.