Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3 x TgAD and 2 x TgAD mice
Intraneuronal accumulation of C99 contributes to synaptic alterations, apathy-like behavior, and spatial learning deficits in 3 x TgAD and 2 x TgAD mice
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DOI：
10.1016/j.neurobiolaging.2018.06.038
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发表时间：
2018-11-01
影响因子：
4.2
通讯作者：
Pardossi-Piquard, Raphaelle
中科院分区：
文献类型：
--
作者：
Bourgeois, Alexandre;Lauritzen, Inger;Pardossi-Piquard, Raphaelle
三重转基因小鼠模型（3x TgAD：APP（swe）、Tau（P301L）、PS1（M146V））重现了淀粉样蛋白β（A β）和tau相关病变以及突触和记忆缺陷。在这些小鼠中，我们报道了早期的冷漠样行为和突触可塑性的改变，伴随着C99在下托神经元内的积累。为了描述C99对上述表型的真正贡献，我们产生了积累C99而没有Ab沉积或tau过度磷酸化的双转基因小鼠（2 x TgAD：APPswe，TauP301L），并将它们与3 x TgAD小鼠进行比较。在这里，我们表明，TgAD小鼠显示类似的减少，在长时程增强和自发运动活动的活动测定表明，突触的改变和冷漠样行为可能与C99，而不是抗体。然而，空间学习的改变，评估的Morris水迷宫任务，在3 × TgAD比在2 × TgAD更明显，这表明，抗体和C99有助于在收购的空间信息的缺陷。最后，即使在男性中观察到类似的结果，女性的认知和非认知缺陷也更严重。(C)2018爱思唯尔公司All rights reserved.
The triple transgenic mouse model (3 x TgAD: APP(swe), Tau(P301L), PS1(M146V)) recapitulates both amyloid beta (A beta)- 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 (2 x TgAD: APPswe, TauP301L) that accumulate C99 without Ab deposition or hyperphosphorylation of tau and compared them to 3 x TgAD mice. Here, we show that both TgAD mice display similar decreases in long-term potentiation and in spontaneous locomotor 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 3 x TgAD than in 2 x TgAD, 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. (C) 2018 Elsevier Inc. All rights reserved.