Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice
Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice
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APP/PS1 转基因 AD 小鼠小胶质细胞的多种炎症特征和改变的神经图像
DOI：
10.1016/j.brainresbull.2020.01.003
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Yuan, Qionglan
中科院分区：
文献类型：
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作者：
Liu, Lifen;Liu, Yutong;Yuan, Qionglan
据信，阿尔茨海默病 (AD) 的 β 斑块先于认知缺陷或临床表现数十年。然而，用于 AD 疾病早期诊断的经过验证的生物标志物仍然无法获得。在本研究中，我们将基于 MRI 的神经图像和 TgAPP/PS1 小鼠 Aβ 沉积早期过程中神经胶质反应和细胞因子改变、神经发生的组织学评估结合起来，以寻找 AD 的潜在早期生物标志物。我们发现，小胶质细胞和星形胶质细胞在 6 个月大时最初被激活并聚集在 Aβ 斑块周围，并在 6-12 个月大时随着年龄的增长而显着增加。共聚焦显微镜分析显示，在 6 个月大的 TgAPP/PS1 小鼠中，小胶质细胞而不是星形胶质细胞开始吞噬 All，这一点可以通过 Iba1 阳性小胶质细胞而不是 GFAP 阳性星形胶质细胞中的细胞内 Aβ 来证明。与这些观察结果同时，我们发现在6-12月龄时，主要成簇的小胶质细胞显着上调促炎因子（包括TNF-α、iNOS和IL-1β）以及抗炎细胞因子（包括IL-4、TGF-β和细胞外保护基质YM-1和精氨酸酶1（Arg1））的产生。有趣的是，反应性星形胶质细胞不表达这些细胞因子以及 YM-1 和 Arg1。这些结果可能表明小胶质细胞而不是星形胶质细胞在 AD 早期清除 Aβ 和神经炎症方面发挥着至关重要的作用。此外，在 Aβ 沉积之前，3 个月大的 TgAPP/PS1 小鼠中，BrdU 标记的神经干细胞和双皮质素标记的未成熟神经元的数量显着减少。最后，DTI 证实海马齿状回各向异性分数 (FA) 的减少，而 rs-MRI 显示 TgAPP/PS1 小鼠 6 个月时体感皮层-尾壳核和岛叶网络的连接性增加。这些发现为诊断 AD 疾病的早期生物标志物提供了线索。
A beta plaques of Alzheimer's disease (AD) are believed to precede cognitive deficits or clinical manifestation by decades. However, validated biomarkers for early diagnosis of the AD disease are still not available. In this present study, we combined MRI-based neuroimages and histological assessment of the glial response and altered cytokines, neurogenesis during the early course of A beta deposits in TgAPP/PS1 mice to find potential early biomarkers for AD. We found that microglia and astrocytes were initially activated and clustered around A beta plaques at the age of 6 months and significantly increased with age from 6-12 months of age. Confocal microscope analysis revealed that microglia not astrocytes began to phagocytose All in 6-month-old TgAPP/PS1 mice, evidenced by the intracellular A beta in Iba1 positive microglia not in GFAP positive astrocytes. In parallel with these observations, we found that mainly clustered microglia significantly upregulated the production of proinflammatory factors including TNF-alpha, iNOS and IL-1 beta, and anti-inflammatory cytokines including IL-4, TGF-beta and extracellular protecting matrix YM-1 and enzyme arginase 1 (Arg1) at 6-12 months of age. Interestingly, reactive astrocyte did not express these cytokines and YM-1 and Arg1. These results may suggest that microglia rather than astrocytes play crucial roles in clearing A beta and neuroinflammation in early stage of AD. In addition, the number of neural stem cells labeled by BrdU and immature neurons labeled by doublecortin was significantly decreased in 3-month-old TgAPP/PS1 mice ahead of A beta deposits. Finally, DTI conforms that reduced fractional anisotropy (FA) in dentate gyrus of hippocampus and rs-MRI shows an increased connectivity in the networks of somatosensory cortex-caudoputamen and insula in TgAPP/PS1 mice at 6 months. These findings provide a clue to early biomarkers for diagnosis of the AD disease.