Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice.
Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice.
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DOI：
10.1194/jlr.ra119000479
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发表时间：
2020-10
影响因子：
6.5
通讯作者：
Sonntag WE
中科院分区：
文献类型：
--
作者：
Parks EE;Logan S;Yeganeh A;Farley JA;Owen DB;Sonntag WE
随着年龄的增长，认知能力下降是一个有害的过程，可能会降低生活质量。多种因素已被确定为认知功能下降的原因，但总体病因尚不清楚。在这里，我们假设认知功能障碍在一定程度上是通过炎性细胞因子水平的增加来调节的，这些细胞因子改变了别孕酮(allopregnanolone，大脑中一种重要的神经类固醇)的水平。我们研究了4月龄和24月龄雄性C57BL/6小鼠体内AllP的水平和调节，以及补充AllP对认知功能的影响。随着年龄的增长，参与allP合成途径的酶的表达减少，皮质酮(Cort)的合成增加。补充AllP可改善认知功能。有趣的是，与对照组相比，在幼年动物体内注射白介素6(IL-6)显著减少了allP的产生。值得注意的是，用其天然抑制剂--可溶性膜糖蛋白130抑制IL-6可显著改善老年小鼠的空间记忆。这些发现得到了原代培养的小鼠星形胶质细胞体外实验的支持，表明IL-6减少了allP的产生，增加了皮质醇的水平。我们的结果表明，与年龄相关的IL-6水平的增加降低了孕酮底物的可获得性，导致了allP水平的下降和皮质醇的增加。此外，我们的结果表明，在炎性细胞因子和年龄相关的认知功能下降之间，allP是一个关键的联系。
Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.