Characterization of cognition alteration across the course of the disease in APP751SL mice with parallel estimation of cerebral Aβ deposition
Characterization of cognition alteration across the course of the disease in APP751SL mice with parallel estimation of cerebral Aβ deposition
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DOI：
10.1016/j.bbr.2009.02.005
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发表时间：
2009-07-19
影响因子：
2.7
通讯作者：
Micheau, Jacques
中科院分区：
文献类型：
--
作者：
Blanchard, Julie;Decorte, Laurence;Micheau, Jacques
目前的阿尔茨海默病转基因小鼠模型是研究神经病理损害、神经退行性变和临床症状之间关系的相关工具。然而，解决Aβ沉积和认知退化之间的关系需要仔细调整年龄，以破译潜在的损伤机制并确定潜在的治疗靶点。在本工作中，我们对APP(751SL)转基因小鼠模型进行了详细的行为分析，测试了6个年龄点(从2到19-20个月)，并同时估计了大脑Aβ的沉积。免疫组织化学研究表明，Aβ(17-24)在几个大脑结构中快速发展，达到大多数结构，在7-8个月龄时达到最高水平。行为学实验表明，APP751SL小鼠的一些一般功能(肌肉力量、运动活动)发生了变化，而其他功能(焦虑、探索)则被保留了下来。食欲操作条件反射的获得和消退被用来评估早期学习缺陷。海马区而不是背外侧纹状体损毁显示出延缓消退。尽管在获得操作性条件反射任务的5-6个月时发现了一些学习缺陷，但在7-8个月大的小鼠中观察到了更强烈的消亡损伤。事实上，空间记忆缺陷与学习诱导的Zif268激活的选择性海马区CA1损伤有关。因为这个小鼠模型表现出逐渐的记忆缺陷，所以它有机会研究导致认知衰退的分子和细胞机制的时间进程。(C)2009爱思唯尔B.V.保留所有权利。
Current transgenic mouse models of Alzheimer disease constitute a relevant tool to examine the relationships between neuropathological lesions, neurodegeneration and clinical syndromes. Nevertheless, addressing the relation between A beta deposition and cognition deterioration requires careful adjustment for age to decipher underlying mechanisms of impairments and identify potential therapeutic targets. In the present work we have carried out a detailed behavioral analysis of the APP(751SL) transgenic mouse model testing 6 age-points (from 2 to 19-20 months) and estimating in parallel the cerebral A beta deposition. The immunohistochemistry study indicated a fast progression of A beta(17-24) staining in several brain structures that reached for most of them, a maximal level at 7-8 months of age. Behavioral experiments showed that APP751SL mice displayed alterations in some general functions (muscular strength, motor activity) whereas other functions are preserved (anxiety, exploration). Acquisition and extinction of an appetitive operant conditioning were used to assess early learning deficits. Hippocampal but not dorsolateral striatal lesion was shown to delay extinction. Although some learning deficits were detected at 5-6 months in the acquisition of the operant conditioning task, more robust impairments in extinction were observed in 7-8-month-old mice. Indeed, spatial memory deficit was associated to a selective hippocampal CA1 impairment of learning-induced Zif268 activation. Because this mouse model displayed gradual memory deficits it gives the opportunity to investigate the temporal progression of molecular and cellular mechanisms that induce cognitive decline. (C) 2009 Elsevier B.V. All rights reserved.