Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease
Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease
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DOI：
10.1016/j.neurobiolaging.2010.05.027
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发表时间：
2012-01-01
影响因子：
4.2
通讯作者：
Wirths, Oliver
中科院分区：
文献类型：
--
作者：
Jawhar, Sadim;Trawicka, Anna;Wirths, Oliver
在本报告中，我们扩展了先前在5XFAD小鼠模型中的发现，并证明这些小鼠除了在高架十字迷宫任务中表现出的工作记忆缺陷和焦虑水平降低外，还具有年龄依赖性运动表型。采用多种N-和C-末端特异性A β抗体，早在3月龄时就观察到了丰富的神经元内和斑块相关病理学，包括焦谷氨酸A β的积累。使用无偏体视学，我们证明了5XFAD小鼠在皮层的第5层中产生了显著的选择性神经元损失，使总额叶皮层和海马的总神经元数量不受影响。这一观察结果与神经元内A β肽仅在皮质层5中积累一致，但在CA 1中不积累，尽管APP表达水平相当。运动表型与丰富的脊髓病理学相关，如丰富的神经元内A β积累和细胞外斑块沉积所证明的。此外，与APP/PS1 KI小鼠模型相比，5XFAD小鼠发生了可能导致行为缺陷的年龄依赖性轴突病。(C)© 2012 IBRO版权所有。
In the present report, we extend previous findings in the 5XFAD mouse model and demonstrate that these mice develop an age-dependent motor phenotype in addition to working memory deficits and reduced anxiety levels as demonstrated in an elevated plus maze task. Employing a variety of N- and C-terminal specific A beta antibodies, abundant intraneuronal and plaque-associated pathology, including accumulation of pyroglutamate A beta, was observed as early as the age of 3 months. Using unbiased stereology, we demonstrate that the 5XFAD mice develop a significant selective neuron loss in layer 5 of the cortex, leaving the overall neuron number of the total frontal cortex and hippocampus unaffected. This observation coincides with the accumulation of intraneuronal A beta peptides only in cortical Layer 5, but not in CA1, despite comparable APP expression levels. The motor phenotype correlates with abundant spinal cord pathology, as demonstrated by abundant intraneuronal A beta accumulation and extracellular plaque deposition. In addition, comparable to the APP/PS1KI mouse model, 5XFAD mice develop an age-dependent axonopathy likely contributing to the behavioral deficits. (C) 2012 IBRO All rights reserved.