Petrasek Tomas, Vojtechova Iveta, Lobellova Veronika, Popelikova Anna, Janikova Martina, Brozka Hana, Houdek Pavel, Sladek Martin, Sumova Alena, Kristofikova Zdenka, Vales Karel, Stuchlík Ales
Department of Neurophysiology of Memory, Institute of Physiology of the Czech Academy of Sciences, Prague, Czechia.
National Institute of Mental Health, Klecany, Czechia.
Front Aging Neurosci. 2018 Aug 28;10:250. doi: 10.3389/fnagi.2018.00250. eCollection 2018.
The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4-7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene was found to be increased in the parietal cortex and cerebellum, while expression was not changed. The clock-controlled gene expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.
麦吉尔-R-Thy1-APP转基因大鼠是家族性阿尔茨海默病（AD）的动物模型。该模型反映了该疾病的几个神经病理学特征，包括β-淀粉样蛋白的积累和淀粉样斑块的形成（仅在纯合动物中）、神经炎症以及甚至在斑块形成之前认知功能的逐渐衰退，尽管它缺乏在AD患者中观察到的tau病变。本研究的目的是全面表征纯合模型，重点是其在已知受AD患者影响的几个行为领域中的表面效度，包括认知功能、运动协调、情绪、社交能力和昼夜活动模式。在行为层面，我们发现4至7月龄的纯合动物在自发探索中的运动活动正常，但存在平衡和步态协调问题、焦虑增加以及空间认知严重受损。麦吉尔大鼠的社会行为和超声交流特征发生了改变，但没有普遍的社交退缩。麦吉尔大鼠的昼夜节律也发生了变化，自由运行周期缩短，主观夜间的总活动增加，在非活动期没有睡眠障碍的迹象。发现昼夜节律钟基因在顶叶皮质和小脑中的表达增加，而 表达没有变化。发现生物钟控制基因在顶叶皮质和海马中的表达升高，这可能导致了观察到的昼夜节律表型变化。我们得出结论，麦吉尔大鼠模型的表型不仅限于认知领域，还包括步态问题、情绪、社会行为和昼夜节律的变化。我们的研究结果表明，该模型对于开发不仅针对记忆衰退而且针对其他降低AD患者生活质量的症状的新治疗方法应该是有用的。
