Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice
Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice
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DOI：
10.1111/acel.12873
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发表时间：
2019-02-01
期刊：
影响因子：
7.8
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
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作者：
Belfiore, Ramona;Rodin, Alexis;Oddo, Salvatore
淀粉样蛋白(A)和纤维缠结的积累，以及神经炎症和记忆力丧失，是阿尔茨海默病(AD)的特征。经过近15年的时间，3xTg-AD小鼠仍然是AD最常用的转基因模型之一。越来越多的证据表明，3xTg-AD小鼠的表型随着时间的推移发生了变化，关于病理或认知缺陷的发病报告在文献中很明显。在这里，我们评估了2个月、6个月、12个月和20个月大的雌性3xTg-AD和非转基因(非Tg)小鼠的A和tau负荷、神经炎症和认知变化。我们发现，在分析的小鼠中，有80%的小鼠在6个月大的时候在尾侧海马区有A斑块，而在12个月大的小鼠中100%的小鼠在海马区有A斑块。皮质A斑块在12个月龄时首次被检测到，包括内嗅皮层。在6月龄小鼠的海马区，Ser202/Thr205和Ser422有明显的Tau磷酸化，而在这个年龄段只有50%的小鼠在Thr212/Ser214有Tau的磷酸化。神经炎症首先出现在6个月大的小鼠身上，并随着年龄的增长而增加。这些神经病理变化显然与进行性认知能力下降有关，这种情况在6个月大的时候就开始显现，随着年龄的增长，情况变得更加严重。这些数据表明，在雌性3xTg-AD小鼠中，AD样病理的进展是一致的和可预测的，并将促进使用这些小鼠进行未来研究的设计。
Accumulation of amyloid- (A) and fibrillary tangles, as well as neuroinflammation and memory loss, are hallmarks of Alzheimer's disease (AD). After almost 15years from their generation, 3xTg-AD mice are still one of the most used transgenic models of AD. Converging evidence indicates that the phenotype of 3xTg-AD mice has shifted over the years and contradicting reports about onset of pathology or cognitive deficits are apparent in the literature. Here, we assessed A and tau load, neuroinflammation, and cognitive changes in 2-, 6-, 12-, and 20-month-old female 3xTg-AD and nontransgenic (NonTg) mice. We found that similar to 80% of the mice analyzed had A plaques in the caudal hippocampus at 6months of age, while 100% of them had A plaques in the hippocampus at 12months of age. Cortical A plaques were first detected at 12months of age, including in the entorhinal cortex. Phosphorylated Tau at Ser202/Thr205 and Ser422 was apparent in the hippocampus of 100% of 6-month-old mice, while only 50% of mice showed tau phosphorylation at Thr212/Ser214 at this age. Neuroinflammation was first evident in 6-month-old mice and increased as a function of age. These neuropathological changes were clearly associated with progressive cognitive decline, which was first apparent at 6months of age and became significantly worse as the mice aged. These data indicate a consistent and predictable progression of the AD-like pathology in female 3xTg-AD mice, and will facilitate the design of future studies using these mice.