APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy
APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy
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DOI：
10.1007/s00401-009-0539-7
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发表时间：
2009-06-01
影响因子：
12.7
通讯作者：
Bayer, Thomas A.
中科院分区：
文献类型：
--
作者：
Breyhan, Henning;Wirths, Oliver;Bayer, Thomas A.
阿尔茨海默病（Alzheimer's disease，AD）是一种以记忆障碍和人格改变为主要临床表现的疾病，其发病机制中存在着重要的Abeta蓄积作用。然而，这种有毒活动的模式仍然是一个科学争论的问题。我们使用APP/PS1 KI小鼠模型用于AD，因为它是迄今为止唯一的在1岁时发生50%海马CA 1神经元损失的模型。以前，我们已经证明，这种模型在6个月大的时候就出现了严重的学习缺陷。这一观察结果促使我们更详细地研究这个时间点的解剖学和细胞基础。在目前的报告中，我们观察到，在6个月大的时候，已经有33%的CA 1神经元丢失和18%的海马萎缩，以及长时程增强的急剧减少和成对脉冲易化的破坏。有趣的是，在4个月大时，CA 1中没有长时程增强缺陷。这伴随着突触前和突触后标记物水平的降低。我们还观察到，神经元内和不同的Abeta肽，包括N-修饰的，纤维状和寡聚Abeta种类的总量增加，并与CA 1神经元的损失相吻合。总体而言，这些数据为在该AD小鼠模型中在6月龄时观察到的稳健的工作记忆缺陷提供了基础。
Abeta accumulation has an important function in the etiology of Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and changes in personality. However, the mode of this toxic activity is still a matter of scientific debate. We used the APP/PS1KI mouse model for AD, because it is the only model so far which develops 50% hippocampal CA1 neuron loss at the age of 1 year. Previously, we have shown that this model develops severe learning deficits occurring much earlier at the age of 6 months. This observation prompted us to study the anatomical and cellular basis at this time point in more detail. In the current report, we observed that at 6 months of age there is already a 33% CA1 neuron loss and an 18% atrophy of the hippocampus, together with a drastic reduction of long-term potentiation and disrupted paired pulse facilitation. Interestingly, at 4 months of age, there was no long-term potentiation deficit in CA1. This was accompanied by reduced levels of pre- and post-synaptic markers. We also observed that intraneuronal and total amount of different Abeta peptides including N-modified, fibrillar and oligomeric Abeta species increased and coincided well with CA1 neuron loss. Overall, these data provide the basis for the observed robust working memory deficits in this mouse model for AD at 6 months of age.