Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept).
Impaired attention in the 3xTgAD mouse model of Alzheimer's disease: rescue by donepezil (Aricept).
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DOI：
10.1523/jneurosci.5242-10.2011
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发表时间：
2011-03-02
期刊：
影响因子：
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通讯作者：
Saksida LM
中科院分区：
文献类型：
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作者：
Romberg C;Mattson MP;Mughal MR;Bussey TJ;Saksida LM
具有丰富的β-淀粉样蛋白和/或异常磷酸化的tau的阿尔茨海默病（AD）的几种小鼠模型发展记忆障碍。然而，多个非记忆的认知领域，如注意力和执行控制也受到损害的早期AD个人。目前，尚不清楚β-淀粉样前体蛋白（APP）和tau的突变是否足以在该疾病的小鼠模型中引起类似的AD样注意力缺陷。为了解决这个问题，我们测试了3xTgAD小鼠（表达APPswe，PS1 M146 V和tauP 301 L突变）和野生型对照小鼠的注意力和反应控制的新开发的基于触摸屏的5选择系列反应时间测试。当任务的注意力需求高时，3xTgAD小鼠对短的、空间上不可预测的刺激的注意力不太准确，并且也表现出比野生型小鼠做出更持久反应的一般趋势。3xTgAD小鼠的注意力障碍在两个方面与AD患者的注意力障碍相当;首先，尽管3xTgAD小鼠最初的反应与野生型小鼠一样准确，但它们随后未能在任务持续时间内保持注意力;其次，胆碱酯酶抑制剂多奈哌齐（安理申）增强了保持注意力的能力。这些发现表明，家族性AD突变不仅影响记忆，而且还导致注意力的显著损害，注意力是由前额叶皮层及其传入支持的认知领域。由于注意力缺陷可能会影响记忆编码和其他认知能力，我们的研究结果对评估AD动物模型的疾病机制和治疗方法具有重要意义。
Several mouse models of Alzheimer’s Disease (AD) with abundant β-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the β-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V and tauP301L mutations) and wild type control mice on a newly-developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects; first, although 3xTgAD mice initially responded as accurately as wild type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.