Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.
Physiol Behav. 2022 Jun 1;250:113787. doi: 10.1016/j.physbeh.2022.113787. Epub 2022 Mar 26.
Agitation, which comprises verbal or physical aggression and hyperactivity, is one of the most frequent neuropsychiatric symptoms observed in patients with Alzheimer's disease (AD). It often co-occurs with dysregulated circadian rhythms. Current medications are associated with serious adverse effects, and novel therapeutics are therefore needed. Rodent models can be instrumental to provide a first signal for potential efficacy of novel drug candidates. Longitudinal data assessing the face validity of such models for AD-related agitation are largely missing. We employed telemeterized APPswe mice, a frequently used AD transgenic mouse line overexpressing the human beta-amyloid precursor protein (APP) with the Swedish KM670/671NL mutation, to study the occurrence and progression of changes in reactive aggressive behavior as well as the circadian profile of locomotor activity and body temperature. Analysis was conducted between 5 and 11 months of age, at regular 2-months intervals. The aggressivity of all mice was highest at 5 months and waned with increasing age. APPswe mice were more aggressive than WT at 5 and 7 months of age. The locomotor activity and body temperature of WT mice declined with increasing age, while that of APPswe mice remained rather constant. This genotype difference was solely evident during the active, dark phase. APPswe mice did not display a phase shift of their circadian rhythms. We conclude that the APPswe mouse line can recapitulate some of the behavioral disturbances observed in AD, including an agitation-relevant phenotype characterized by active phase hyperactivity and aggressivity. It does not recapitulate the nighttime disturbances (also characterized by hyperactivity) and the shift of circadian rhythms observed in AD patients. Therefore, the APPswe strain could be used at specific ages to model a subset of agitation-relevant behavioral problems and to test the modulatory effects of drugs.
激越，包括言语或躯体攻击和多动，是阿尔茨海默病（AD）患者最常见的神经精神症状之一。它常与昼夜节律失调并存。目前的药物与严重的不良反应相关，因此需要新的治疗方法。啮齿动物模型可以为新型候选药物的潜在疗效提供初步信号。用于评估 AD 相关激越的此类模型的表面有效性的纵向数据在很大程度上缺失。我们使用遥测 APPswe 小鼠，一种常用的 AD 转基因小鼠系，过表达具有瑞典 KM670/671NL 突变的人类β淀粉样前体蛋白（APP），以研究反应性攻击行为变化的发生和进展，以及运动活动和体温的昼夜节律特征。分析在 5 至 11 个月龄之间进行，每隔 2 个月进行一次。所有小鼠的攻击性在 5 个月时最高，随着年龄的增长而减弱。5 个月和 7 个月时，APPswe 小鼠比 WT 更具攻击性。WT 小鼠的运动活动和体温随年龄的增长而下降，而 APPswe 小鼠的运动活动和体温则相对保持不变。这种基因型差异仅在活跃的暗期明显。APPswe 小鼠的昼夜节律没有发生相位转移。我们得出结论，APPSwe 小鼠系可以再现 AD 中观察到的一些行为障碍，包括以活跃期多动和攻击性为特征的与激越相关的表型。它不能再现 AD 患者夜间的障碍（也以多动为特征）和昼夜节律的转移。因此，APPSwe 品系可以在特定年龄用于模拟与激越相关的行为问题的子集，并测试药物的调节作用。
