Dumont Julie R, Sheppard Paul A S, Fodor Chris, Coto M Alexander, Yang Sabrina, Saito Takashi, Saido Takaomi C, Rylett R Jane, Prado Marco A M, Bussey Timothy J, Saksida Lisa M, Prado Vania F
BrainsCAN, Western University, London, Ontario, Canada.
Robarts Research Institute, Western University, London, Ontario, Canada.
Genes Brain Behav. 2025 Jun;24(3):e70024. doi: 10.1111/gbb.70024.
Alzheimer's disease is a debilitating neurodegenerative condition characterized by amyloid beta plaques and tau neurofibrillary tangles, which leads to progressive cognitive decline. Several new mouse models of fast amyloid deposition have been generated with compound mutations, but how these affect high-level cognitive function is still not fully understood. Four cohorts of a second-generation amyloid precursor protein knock-in mouse model, App, which develops aggressive amyloidopathy, were compared with two different control groups that do not produce plaques (App and wildtype littermates), on touchscreen-based tests of learning and cognitive flexibility. App mice learned to discriminate between two visual stimuli during the pairwise visual discrimination (PVD) task but were impaired when the reward contingencies were reversed (the PVR task). Analyses of the correction trials indicated perseverative behavior. One cohort was further tested on the touchscreen Extinction test, which isolates the ability to withhold responding to a previously rewarded stimulus. The App mice extinguished their responding no differently than the App control group. These results indicate that compound mutations in App driving fast accumulation of plaques in this mouse model impair cognitive flexibility and may serve as a preclinical target for putative therapeutic drugs.
阿尔茨海默病是一种使人衰弱的神经退行性疾病，其特征为β淀粉样蛋白斑块和tau神经原纤维缠结，会导致进行性认知衰退。通过复合突变已构建了几种新的快速淀粉样蛋白沉积小鼠模型，但这些模型如何影响高级认知功能仍未完全明确。在基于触摸屏的学习和认知灵活性测试中，将第二代淀粉样前体蛋白敲入小鼠模型（App，该模型会发展出侵袭性淀粉样病变）的四个队列与两个不产生斑块的不同对照组（App和野生型同窝小鼠）进行了比较。在成对视觉辨别（PVD）任务中，App小鼠学会了区分两种视觉刺激，但当奖励条件反转时（PVR任务），它们的表现受损。对校正试验的分析表明存在持续行为。对其中一个队列进一步进行了触摸屏消退测试，该测试可分离出抑制对先前奖励刺激做出反应的能力。App小鼠的反应消退情况与App对照组没有差异。这些结果表明，在该小鼠模型中驱动斑块快速积累的App复合突变会损害认知灵活性，可能作为潜在治疗药物的临床前靶点。
