Szabó Adrienn, Farkas Szidónia, Fazekas Csilla, Correia Pedro, Chaves Tiago, Sipos Eszter, Makkai Bernadett, Török Bibiána, Zelena Dóra
Centre for Neuroscience, Szentágothai Research Centre, Institute of Physiology, Medical School, University of Pécs, 7624 Pécs, Hungary.
Laboratory of Behavioral and Stress Studies, Institute of Experimental Medicine, 1083 Budapest, Hungary.
Biomedicines. 2023 Jan 18;11(2):262. doi: 10.3390/biomedicines11020262.
The prevalence of Alzheimer's disorder (AD) is increasing worldwide, and the co-morbid anxiety is an important, albeit often neglected problem, which might appear early during disease development. Animal models can be used to study this question. Mice, as prey animals, show an innate defensive response against a predator odor, providing a valuable tool for anxiety research. Our aim was to test whether the triple-transgenic mice model of AD shows signs of innate anxiety, with specific focus on the temporal appearance of the symptoms. We compared 3xTg-AD mice bearing human mutations of amyloid precursor protein, presenilin 1, and tau with age-matched controls. First, separate age-groups (between 2 and 18 months) were tested for the avoidance of 2-methyl-2-thiazoline, a fox odor component. To test whether hypolocomotion is a general sign of innate anxiety, open-field behavior was subsequently followed monthly in both sexes. The 3xTg-AD mice showed more immobility, approached the fox odor container less often, and spent more time in the avoidance zone. This effect was detectable already in two-month-old animals irrespective of sex, not visible around six months of age, and was more pronounced in aged females than males. The 3xTg-AD animals moved generally less. They also spent less time in the center of the open-field, which was detectable mainly in females older than five months. In contrast to controls, the aged 3xTg-AD was not able to habituate to the arena during a 30-min observation period irrespective of their sex. Amyloid beta and phospho-Tau accumulated gradually in the hippocampus, amygdala, olfactory bulb, and piriform cortex. In conclusion, the early appearance of predator odor- and open space-induced innate anxiety detected already in two-month-old 3xTg-AD mice make this genetically predisposed strain a good model for testing anxiety both before the onset of AD-related symptoms as well as during the later phase. Synaptic dysfunction by protein deposits might contribute to these disturbances.
阿尔茨海默病（AD）在全球的患病率正在上升，而共病焦虑是一个重要但常常被忽视的问题，它可能在疾病发展的早期就出现。动物模型可用于研究这个问题。小鼠作为被捕食动物，对捕食者气味表现出天生的防御反应，为焦虑研究提供了一个有价值的工具。我们的目的是测试AD的三转基因小鼠模型是否表现出天生焦虑的迹象，特别关注症状的出现时间。我们将携带淀粉样前体蛋白、早老素1和tau人类突变的3xTg-AD小鼠与年龄匹配的对照组进行比较。首先，对不同年龄组（2至18个月）的小鼠进行测试，以观察它们对狐狸气味成分2-甲基-2-噻唑啉的回避情况。为了测试运动减少是否是天生焦虑的普遍迹象，随后每月对两性的旷场行为进行跟踪观察。3xTg-AD小鼠表现出更多的静止不动，更少接近狐狸气味容器，并且在回避区域花费更多时间。这种效应在两个月大的动物中就可以检测到，与性别无关，在六个月左右不可见，并且在老年雌性中比雄性更明显。3xTg-AD动物总体活动较少。它们在旷场中心花费的时间也较少，这主要在五个月以上的雌性中可以检测到。与对照组不同，无论性别如何，老年3xTg-AD小鼠在30分钟的观察期内都无法适应实验场地。淀粉样β蛋白和磷酸化tau蛋白在海马体、杏仁核、嗅球和梨状皮质中逐渐积累。总之，在两个月大的3xTg-AD小鼠中就已检测到的对捕食者气味和开放空间诱导的天生焦虑的早期出现，使这种具有遗传易感性的品系成为在AD相关症状出现之前以及后期阶段测试焦虑的良好模型。蛋白质沉积导致的突触功能障碍可能是这些干扰的原因。
