Amyloid Deposition and Inflammation in APPswe/PS1dE9 Mouse Model of Alzheimer's Disease
Amyloid Deposition and Inflammation in APPswe/PS1dE9 Mouse Model of Alzheimer's Disease
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DOI：
10.2174/156720509790147070
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发表时间：
2009-12-01
影响因子：
2.1
通讯作者：
Le, Yingying
中科院分区：
文献类型：
--
作者：
Ruan, Lingfei;Kang, Zhoujun;Le, Yingying
阿尔茨海默病（AD）的特征在于与慢性炎症相关的淀粉样斑块和神经元缠结。APPswe/PS1 dE 9是携带淀粉样前体蛋白和早老素-1的突变转基因的AD小鼠模型。淀粉样蛋白沉积存在于该小鼠模型的生命早期阶段。然而，炎症的进展及其与淀粉样蛋白沉积的关系尚未得到表征。在这里，我们发现淀粉样蛋白斑块在4个月大时就存在，并随着年龄的增长而增加。CD 11b阳性小胶质细胞簇在4月龄时出现在海马和新皮质中，并随年龄增加而增加。6月龄后，在海马和皮质中观察到胶质细胞酸性蛋白（GFAP）阳性星形胶质细胞，并随年龄增加而增加。用CD 11b/GFAP抗体和硫磺素S双重染色显示聚集的小胶质细胞和星形胶质细胞与淀粉样斑块密切相关。TNF-α的表达在8月龄时检测到，而IL-1 β、IL-6和MCP-1在10月龄时检测到。这些细胞因子随着年龄的增长而增加。细胞特异性标志物和细胞因子双重免疫组化染色显示活化的小胶质细胞和小部分活化的星形胶质细胞表达TNF-α、IL-1 β、IL-6和MCP-1。MCP-1也在神经元中表达，这支持了最近的发现，即MCP-1在AD患者的神经元中表达增加。这些结果表明，淀粉样蛋白斑块及其相关的炎症反应在生命早期发展，并随着年龄的增长而逐渐增加，活化的胶质细胞和神经元都参与了AD的慢性炎症。APPswe/PS1 dE 9模型为研究AD的发病机制和新的治疗方法提供了一种新的手段。
Alzheimer's disease (AD) is characterized by amyloid plaques and neurofibrillary tangles associated with chronic inflammation. APPswe/PS1dE9 is an AD mouse model bearing mutant transgenes of amyloid precursor protein and presenilin-1. Amyloid deposition is present in this mouse model at early stage of life. However, the progression of inflammation and its relationship with amyloid deposition have not been characterized. Here we showed that amyloid plaques were present at 4 months of age and increased with age. CD11b-positive microglia clusters appeared in hippocampus and neocortex at 4 months of age and increased with age. Clustered glial fibrillary acidic protein (GFAP)-positive astrocytes were observed in hippocampus and cortex after 6 months of age and increased with age. Double staining with CD11b/GFAP antibody and thioflavin S showed clustered microglia and astrocytes were in close association with amyloid plaques. Expression of TNF-alpha was detected at 8 months of age, while IL-1 beta IL-6 and MCP-1 at 10 months. These cytokines increased with age. Double immunostaining of cell specific marker and cytokine indicated TNF-alpha, IL-1 beta, IL-6 and MCP-1 were expressed by activated microglia and a small part of activated astrocytes. MCP-1 was also expressed by neurons, which support recent finding that MCP-1 expression was increased in neurons of AD patient. These results demonstrate amyloid plaques and its associated inflammatory response developed at early stage of life and progressively increased with age, both activated glia and neurons are involved in chronic inflammation in AD. APPswe/PS1dE9 model provides a mean for studying the mechanisms and novel therapeutics for AD.