Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis.
Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis.
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DOI：
10.1186/alzrt124
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发表时间：
2012-06-14
期刊：
影响因子：
--
通讯作者：
Janus C
中科院分区：
文献类型：
--
作者：
Hanna A;Iremonger K;Das P;Dickson D;Golde T;Janus C
目前对阿尔茨海默病(AD)诊断的病理确认仍然是基于尸检发现的实质性淀粉样β蛋白(Aβ)斑块、神经元内神经原纤维缠结和神经元丢失。阿尔茨海默病早期出现的记忆缺陷与内嗅皮层和边缘系统，特别是海马体和杏仁核的结构功能障碍有关。利用过量表达突变的人淀粉样前体蛋白(APP)基因的CRND8转基因小鼠模型，我们评估了海马区依赖的上下文和杏仁核依赖的音调恐惧条件性记忆(FC)，并研究了恐惧记忆指数与Aβ斑块负荷的关系。按照横断面实验设计，对3、6和12个月大的小鼠进行测试，这对应于早期、轻度和严重的Aβ斑块沉积。我们使用了延迟版本的恐惧条件反射范式，在探索训练室的过程中，音调刺激与足部电击共同终止。在完成行为测试后，在每个年龄段评估Aβ斑块负荷。CRDN8小鼠在3个月和6个月时表现出与对照组小鼠相当的情景恐惧记忆，但在12个月大时显著受损。相比之下，在测试的每个年龄段，模型中的音调恐惧记忆都显著受损。Aβ斑块负荷量随着年龄的增长而显著增加，并且与研究年龄段内CRND8小鼠的背景和音调恐惧记忆的整体损害相关。我们的数据扩展了之前的研究，表明其他APP鼠标模型在恐惧条件记忆方面表现出损害，证明这种损害是进行性的，并与Aβ负担的总体增加很好地相关。此外，在识别CRND8和对照小鼠之间的年龄依赖差异方面，音调条件反射测试表现出更高的敏感性，这表明该范式可能特别适用于评估与改善淀粉样变性小鼠模型的记忆相关的潜在疗法的研究。
The current pathological confirmation of the diagnosis of Alzheimer's disease (AD) is still based on postmortem identification of parenchymal amyloid beta (Aβ) plaques, intra-neuronal neurofibrillary tangles, and neuronal loss. The memory deficits that are present in the early stages of AD are linked to the dysfunction of structures in the entorhinal cortex and limbic system, especially the hippocampus and amygdala. Using the CRND8 transgenic mouse model of amyloidosis, which over-expresses a mutant human amyloid precursor protein (APP) gene, we evaluated hippocampus-dependent contextual and amygdala-dependent tone fear conditioned (FC) memory, and investigated the relationship between the fear memory indices and Aβ plaque burden. Mice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aβ plaque deposition, following a cross-sectional experimental design. We used a delay version of the fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of the training chamber. The Aβ plaque burden was evaluated at each age after the completion of the behavioral tests. CRDN8 mice showed context fear memory comparable to control mice at three and six months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Aβ plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age. Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlates well with an overall increase in Aβ burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.
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影响因子：
56.9
作者：
BECHARA, A;TRANEL, D;DAMASIO, AR
通讯作者：
DAMASIO, AR
影响因子：
64.5
作者：
BEACH, ME;HAWKINS, RD;MAYFORD, M
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MAYFORD, M
影响因子：
64.8
作者：
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Morris, RGM
影响因子：
3.9
作者：
Dewachter, I;van Dorpe, J;Van Leuven, F
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Van Leuven, F
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2
作者：
Corcoran, KA;Lu, Y;Maren, S
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Maren, S