Glucocorticoids Facilitate Astrocytic Amyloid-β Peptide Deposition by Increasing the Expression of APP and BACE1 and Decreasing the Expression of Amyloid-β-Degrading Proteases
Glucocorticoids Facilitate Astrocytic Amyloid-β Peptide Deposition by Increasing the Expression of APP and BACE1 and Decreasing the Expression of Amyloid-β-Degrading Proteases
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DOI：
10.1210/en.2011-0145
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发表时间：
2011-07-01
期刊：
影响因子：
4.8
通讯作者：
Bai, Yun
中科院分区：
文献类型：
--
作者：
Wang, Yanyan;Li, Maoquan;Bai, Yun
在大多数情况下，散发性阿尔茨海默病（AD）发病机制的分子机制尚不清楚。AD患者基础皮质醇水平升高提示糖皮质激素（GC）可能有助于AD的发展和/或维持。淀粉样斑块是阿尔茨海默病的标志，它们被认为在阿尔茨海默病的早期过程中起作用。然而，对于应力和气相沉积如何调节它们的形成，人们知之甚少。星形胶质细胞堆积是阿尔茨海默病最早的神经病理改变之一。在这里，我们报道了GC通过增加淀粉样蛋白前体蛋白（APP）和β位点APP切割酶1基因表达来提高星形胶质细胞原代培养中淀粉样蛋白β (A β)的产生。值得注意的是，经双免疫荧光检测，正常中年小鼠服用GC可促进星形胶质细胞中APP和β -位点APP切割酶1的表达。此外，共聚焦显微镜和ELISA结果显示，GC显著降低了体外星形胶质细胞对A β的降解和清除，表明星形胶质细胞的神经保护能力下降。这可能是由于几种A - β降解蛋白酶的减少，如胰岛素降解酶和基质金属蛋白酶-9。这些作用是通过激活GC受体发生的。综上所述，我们的研究结果表明，GC可以增强A β的产生，减少其在星形胶质细胞中的降解，并提供了应激因素与AD之间的分子机制。我们的研究表明，GC可以促进AD的发病，减少老年和早期AD患者的GC将是有益的。（内分泌学152:2704-2715,2011）
In most cases, the molecular mechanism underlying the pathogenesis of sporadic Alzheimer's disease (AD) is unknown. Elevated basal cortisol levels in AD patients suggest that glucocorticoids (GC) may contribute to the development and/or maintenance of AD. Amyloid plaques are the hallmark of AD, and they are considered to play an early role in the AD process. However, little is known about how their formation is regulated by stress and GC. Astrocyte accumulation is one of the earliest neuropathological changes in AD. Here, we report that GC elevated amyloid-beta (A beta) production in primary cultures of astrocytes by increasing amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 gene expression. Notably, GC administered to normal, middle-aged mice promoted the expression of APP and beta-site APP-cleaving enzyme 1 in astrocytes, as determined by double immunofluorescence. Additionally, confocal microscopy and ELISA revealed that GC markedly reduced A beta degradation and clearance by astrocytes in vitro, indicating a decreased neuroprotective capacity of the astrocytes. This may have been due to the decrease of several A beta-degrading proteases, such as insulin-degrading enzyme and matrix metalloproteinase-9. These effects occurred through the activation of GC receptors. Taken together, our results demonstrate that GC can enhance the production of A beta, reduce its degradation in astrocytes, and provide a molecular mechanism linking stress factors to AD. Our study suggests that GC can facilitate AD pathogenesis and that reducing GC in the elderly and early AD patients would be beneficial. (Endocrinology 152: 2704-2715, 2011)