Sanders-Brown Center on Aging, 800 S. Limestone, University of Kentucky, Lexington, KY 40536, USA.
Sanders-Brown Center on Aging, 800 S. Limestone, University of Kentucky, Lexington, KY 40536, USA ; Department of Anatomy and Neurobiology, 800 S. Limestone, University of Kentucky, Lexington, KY 40536, USA.
Alzheimers Res Ther. 2013 May 24;5(3):28. doi: 10.1186/alzrt182. eCollection 2013.
Despite the extensive mechanistic and pathological characterization of the amyloid precursor protein (APP)/presenilin-1 (PS-1) knock-in mouse model of Alzheimer's disease (AD), very little is known about the AD-relevant behavioral deficits in this model. Characterization of the baseline behavioral performance in a variety of functional tasks and identification of the temporal onset of behavioral impairments are important to provide a foundation for future preclinical testing of AD therapeutics. Here we perform a comprehensive behavioral characterization of this model, discuss how the observed behavior correlates with the mechanistic and pathological observations of others, and compare this model with other commonly used AD mouse models.
FOUR DIFFERENT GROUPS OF MICE RANGING ACROSS THE LIFESPAN OF THIS MODEL (TEST GROUPS: 7, 11, 15, and 24 months old) were run in a behavioral test battery consisting of tasks to assess motor function (grip strength, rotor rod, beam walk, open field ambulatory movement), anxiety-related behavior (open field time spent in peripheral zone vs. center zone, elevated plus maze), and cognitive function (novel object recognition, radial arm water maze).
There were no differences in motor function or anxiety-related behavior between APP/PS-1 knock-in mice and wild-type counterpart mice for any age group. Cognitive deficits in both recognition memory (novel object recognition) and spatial reference memory (radial arm water maze) became apparent for the knock-in animals as the disease progressed.
This is the first reported comprehensive behavioral analysis of the APP/PS1 knock-in mouse model of AD. The lack of motor/coordination deficits or abnormal anxiety levels, coupled with the age/disease-related cognitive decline and high physiological relevance of this model, make it well suited for utilization in preclinical testing of AD-relevant therapeutics.
尽管淀粉样前体蛋白（APP）/早老素-1（PS-1）敲入阿尔茨海默病（AD）小鼠模型的机制和病理学特征得到了广泛的研究，但对该模型中与 AD 相关的行为缺陷知之甚少。在各种功能任务中对基线行为表现进行特征描述，并确定行为损伤的时间发生，对于为未来 AD 治疗药物的临床前测试提供基础非常重要。在这里，我们对该模型进行了全面的行为特征描述，讨论了观察到的行为与其他人的机制和病理学观察结果的相关性，并将该模型与其他常用的 AD 小鼠模型进行了比较。
跨越该模型生命周期的四个不同组别的小鼠（测试组：7、11、15 和 24 个月大）在一个行为测试组合中进行测试，该组合包括评估运动功能（握力、转棒、走棒、旷场活动）、焦虑相关行为（旷场时间在周边区域与中心区域的分布、高架十字迷宫）和认知功能（新物体识别、放射臂水迷宫）的任务。
在任何年龄组，APP/PS-1 敲入小鼠与野生型对照小鼠之间在运动功能或焦虑相关行为方面均无差异。随着疾病的进展，敲入动物在两种认知功能（新物体识别的识别记忆和放射臂水迷宫的空间参考记忆）中均出现认知缺陷。
这是首次对 APP/PS1 敲入 AD 小鼠模型进行全面的行为分析。该模型缺乏运动/协调缺陷或异常的焦虑水平，再加上该模型具有与年龄/疾病相关的认知下降和高度的生理相关性，使其非常适合用于 AD 相关治疗药物的临床前测试。
