11β-Hydroxysteroid Dehydrogenase Type 1 Expression Is Increased in the Aged Mouse Hippocampus and Parietal Cortex and Causes Memory Impairments
11β-Hydroxysteroid Dehydrogenase Type 1 Expression Is Increased in the Aged Mouse Hippocampus and Parietal Cortex and Causes Memory Impairments
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DOI：
10.1523/jneurosci.0731-10.2010
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发表时间：
2010-05-19
影响因子：
5.3
通讯作者：
Yau, Joyce L. W.
中科院分区：
文献类型：
--
作者：
Holmes, Megan C.;Carter, Roderick N.;Yau, Joyce L. W.
增加的神经元糖皮质激素暴露可能是啮齿动物和人类认知功能随年龄变化的个体间差异的基础。1型β -羟基类固醇脱氢酶（11 β - hsd1）催化细胞（大脑和其他组织）内活性糖皮质激素的再生，从而增强类固醇的作用。我们研究了11 β - hsd1是否在雄性C57BL/6J小鼠衰老相关的认知缺陷发病机制中发挥作用。我们发现，CA3海马和顶叶皮层中11 β - hsd1水平随着年龄的增长而增加，这与水迷宫中认知能力受损有关。相反，循环皮质酮水平和组织皮质类固醇受体表达都与认知无关。11 β - hsd1升高似乎是因果关系，因为衰老（18个月）雄性转基因小鼠前脑特异性11 β - hsd1过表达（海马体中类似50%）在没有改变循环糖皮质激素水平或其他行为（情感）缺陷的情况下，表现出与年龄相关的过早认知能力下降。因此，前脑中过量的11 β - hsd1是衰老记忆障碍的原因，也是治疗的靶点。
Increased neuronal glucocorticoid exposure may underlie interindividual variation in cognitive function with aging in rodents and humans. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the regeneration of active glucocorticoids within cells (in brain and other tissues), thus amplifying steroid action. We examined whether 11 beta-HSD1 plays a role in the pathogenesis of cognitive deficits associated with aging in male C57BL/6J mice. We show that 11 beta-HSD1 levels increase with age in CA3 hippocampus and parietal cortex, correlating with impaired cognitive performance in the water maze. In contrast, neither circulating corticosterone levels nor tissue corticosteroid receptor expression correlates with cognition. 11 beta-HSD1 elevation appears causal, since aging (18 months) male transgenic mice with forebrain-specific 11 beta-HSD1 overexpression (similar to 50% in hippocampus) exhibit premature age-associated cognitive decline in the absence of altered circulating glucocorticoid levels or other behavioral (affective) deficits. Thus, excess 11 beta-HSD1 in forebrain is a cause of as well as a therapeutic target in memory impairments with aging.