The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease.
The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease.
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DOI：
10.1186/s13041-015-0174-2
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发表时间：
2015-12-04
期刊：
影响因子：
3.6
通讯作者：
Kinoshita A
中科院分区：
文献类型：
--
作者：
Watanabe K;Uemura K;Asada M;Maesako M;Akiyama H;Shimohama S;Takahashi R;Kinoshita A
阿尔茨海默病（AD）的特征是老年斑、主要由淀粉样蛋白- β (Aβ)组成的细胞外沉积物和神经原纤维缠结，这是一种含有过度磷酸化tau的异常细胞内内含物。淀粉样蛋白级联假说认为，a β在脑实质中的沉积引发了一系列导致痴呆的事件。然而，细胞外积累的β肽促进tau蛋白丝细胞内病理变化的分子过程尚不清楚。为了阐明这一过程，我们假设星形胶质细胞可能引发神经元反应，导致tau磷酸化。在这项研究中，我们从星形细胞-神经元相互作用的角度研究了阿尔茨海默病的病理。细胞因子阵列分析显示，Aβ刺激星形胶质细胞释放几种主要与炎症和细胞粘附相关的化学介质。在这些介质中，胰岛素样生长因子（IGF）结合蛋白3 （IGFBP-3）高度上调。western blot分析发现，AD脑组织中IGFBP-3表达升高，荧光显微镜观察到星形胶质细胞中IGFBP-3表达升高。此外，我们用人星形细胞瘤细胞株重现了用Aβ处理后IGFBP-3的增加，发现IGFBP-3通过钙调磷酸酶表达。在AD脑中，western blot分析发现calcalineurin的活化形式增加，荧光显微镜观察到星形胶质细胞中calcalineurin的表达增加。当糖原合成酶激酶3β (GSK-3β)的Ser9磷酸化时，GSK-3β受到控制，tau磷酸化受到抑制。Aβ抑制GSK-3β的磷酸化，导致tau磷酸化。在这项研究中，我们发现IGF-Ι抑制了Aβ诱导的tau磷酸化，尽管IGFBP-3抑制了IGF的这一特性-Ι。结果，IGFBP-3参与了a β诱导的tau磷酸化和细胞死亡。我们的研究表明星形胶质细胞中的钙调磷酸酶被Aβ激活，导致IGFBP-3的释放。我们进一步证明星形胶质细胞产生的IGFBP-3诱导神经元中的tau磷酸化。我们的研究为星形胶质细胞在诱导tau磷酸化中的作用提供了新的见解，并表明IGFBP-3可能是Aβ与tau病理之间的重要联系和重要的治疗靶点。本文的在线版本（doi:10.1186/s13041-015-0174-2）包含补充材料，可供授权用户使用。
Alzheimer’s disease (AD) is characterized by senile plaques, extracellular deposits composed primarily of amyloid–beta (Aβ), and neurofibrillary tangles, which are abnormal intracellular inclusions containing hyperphosphorylated tau. The amyloid cascade hypothesis posits that the deposition of Aβ in the brain parenchyma initiates a sequence of events that leads to dementia. However, the molecular process by which the extracellular accumulation of Aβ peptides promotes intracellular pathologic changes in tau filaments remains unclear. To elucidate this process, we presumed that astrocytes might trigger neuronal reactions, leading to tau phosphorylation. In this study, we examined AD pathology from the perspective of the astrocyte-neuron interaction. A cytokine-array analysis revealed that Aβ stimulates astrocytes to release several chemical mediators that are primarily related to inflammation and cell adhesion. Among those mediators, insulin-like growth factor (IGF)-binding protein 3 (IGFBP-3) was highly upregulated. In AD brains, the expression of IGFBP-3 was found to be increased by western blot analysis, and increased expression of IGFBP-3 was observed in astrocytes via fluorescence microscopy. In addition, we reproduced the increase in IGFBP-3 after treatment with Aβ using human astrocytoma cell lines and found that IGFBP-3 was expressed via calcineurin. In AD brains, the activated forms of calcineurin were found to be increased by western blot analysis, and increased expression of calcineurin was observed in astrocytes via fluorescence microscopy. When Ser9 of glycogen synthase kinase-3β (GSK-3β) is phosphorylated, GSK-3β is controlled and tau phosphorylation is suppressed. Aβ suppresses the phosphorylation of GSK-3β, leading to tau phosphorylation. In this study, we found that IGF-Ι suppressed tau phosphorylation induced by Aβ, although IGFBP-3 inhibited this property of IGF-Ι. As a result, IGFBP-3 contributed to tau phosphorylation and cell death induced by Aβ. Our study suggested that calcineurin in astrocytes was activated by Aβ, leading to IGFBP-3 release. We further demonstrated that IGFBP-3 produced by astrocytes induced tau phosphorylation in neurons. Our study provides novel insights into the role of astrocytes in the induction of tau phosphorylation and suggests that IGFBP-3 could be an important link between Aβ and tau pathology and an important therapeutic target. The online version of this article (doi:10.1186/s13041-015-0174-2) contains supplementary material, which is available to authorized users.