Landfield Philip W, Blalock Eric M, Chen Kuey-Chu, Porter Nada M
Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Curr Alzheimer Res. 2007 Apr;4(2):205-12. doi: 10.2174/156720507780362083.
The original glucocorticoid (GC) hypothesis of brain aging and Alzheimer's disease proposed that chronic exposure to GCs promotes hippocampal aging and AD. This proposition arose from a study correlating increasing plasma corticosterone with hippocampal astrocyte reactivity in aging rats. Numerous subsequent studies have found evidence consistent with this hypothesis, in animal models and in humans. However, several results emerged that were inconsistent with the hypothesis, highlighting the need for a more definitive test with a broader panel of biomarkers. We used microarray analyses to identify a panel of hippocampal gene expression changes that were aging-dependent, and also corticosterone-dependent. These data enabled us to test a key prediction of the GC hypothesis, namely, that the expression of most target biomarkers of brain aging should be regulated in the same direction (increased or decreased) by both GCs and aging. This prediction was decisively contradicted, as a majority of biomarker genes were regulated in opposite directions by aging and GCs, particularly inflammatory and astrocyte-specific genes. Thus, the initial hypothesis of simple positive cooperativity between GCs and aging must be rejected. Instead, our microarray data suggest that in the brain GCs and aging interact in more complex ways that depend on the cell type. Therefore, we propose a new version of the GC-brain aging hypothesis; its main premise is that aging selectively increases GC efficacy in some cell types (e.g., neurons), enhancing catabolic processes, whereas aging selectively decreases GC efficacy in other cell types (e.g., astrocytes), weakening GC anti-inflammatory activity. We also propose that changes in GC efficacy might be mediated in part by cell type specific shifts in the antagonistic balance between GC and insulin actions, which may be of relevance for Alzheimer's disease pathogenesis.
最初关于大脑衰老和阿尔茨海默病的糖皮质激素（GC）假说提出，长期暴露于糖皮质激素会促进海马体衰老和阿尔茨海默病。这一观点源于一项将老年大鼠血浆皮质酮水平升高与海马体星形胶质细胞反应性相关联的研究。随后的大量研究在动物模型和人类中都发现了与该假说一致的证据。然而，也出现了一些与该假说不一致的结果，这凸显了需要用更广泛的生物标志物进行更明确测试的必要性。我们使用微阵列分析来确定一组与衰老相关且也与皮质酮相关的海马体基因表达变化。这些数据使我们能够检验糖皮质激素假说的一个关键预测，即大脑衰老的大多数目标生物标志物的表达应该受到糖皮质激素和衰老的同向调节（增加或减少）。这一预测被明确反驳，因为大多数生物标志物基因受到衰老和糖皮质激素的反向调节，特别是炎症和星形胶质细胞特异性基因。因此，必须摒弃糖皮质激素与衰老之间简单正协同作用的最初假说。相反，我们的微阵列数据表明，在大脑中，糖皮质激素和衰老以更复杂的方式相互作用，这取决于细胞类型。因此，我们提出了糖皮质激素 - 大脑衰老假说的新版本；其主要前提是，衰老选择性地增加某些细胞类型（如神经元）中糖皮质激素的效力，增强分解代谢过程，而衰老选择性地降低其他细胞类型（如星形胶质细胞）中糖皮质激素的效力，削弱糖皮质激素的抗炎活性。我们还提出，糖皮质激素效力的变化可能部分由糖皮质激素与胰岛素作用之间拮抗平衡的细胞类型特异性转变介导，这可能与阿尔茨海默病的发病机制有关。
