IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase.
IL-6 mediated degeneration of forebrain GABAergic interneurons and cognitive impairment in aged mice through activation of neuronal NADPH oxidase.
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DOI：
10.1371/journal.pone.0005518
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Behrens MM
中科院分区：
文献类型：
--
作者：
Dugan LL;Ali SS;Shekhtman G;Roberts AJ;Lucero J;Quick KL;Behrens MM
多项研究表明，在动脉粥样硬化、糖尿病、肥胖、阻塞性睡眠呼吸暂停、高血压和虚弱等重要和普遍不良健康状况的患者中，血浆促炎细胞因子白细胞介素-6 （IL-6）水平升高。反过来，较高的血浆IL-6水平会增加许多与衰老相关的疾病的风险，包括与年龄相关的认知能力下降。然而，IL-6与认知脆弱性之间关联的机制尚不清楚。我们研究了IL-6在幼年（4个月）和老年（24个月）野生型C57BL6和遗传匹配的IL-6 - / -小鼠脑衰老中的作用，并确定IL-6是增加神经细胞超氧化物产生免疫酶nadph氧化酶表达的必要和充分条件，这是由非典型NFκB信号通路介导的。此外，nadph氧化酶产生的超氧化物直接导致了海马和皮质中表达gaba能的小白蛋白（PV）中间神经元的年龄相关性丧失，这些神经元对正常的信息处理、编码和检索至关重要。在空间学习和回忆的三个标准测试中，通过超氧化物歧化酶模拟物的慢性治疗靶向删除IL-6或消除超氧化物，可以预防与年龄相关的pvv中间神经元的损失，并逆转与年龄相关的认知缺陷。目前的研究结果表明，IL-6通过增加神经元nadph氧化酶衍生的超氧化物产生，介导了关键的表达磷酸腺苷gaba能的中间神经元的年龄相关损失，并且这些中间神经元的拯救保留了衰老小鼠的认知表现，这表明外周IL-6水平的升高可能直接和机械地与即使是正常老年人的长期认知缺陷有关。此外，由于pv -中间神经元也选择性地受到常用麻醉剂和药物的影响，我们的研究结果表明，IL-6水平可以通过抑制中间神经元的特定紊乱来预测暴露于这些化合物的老年患者的中枢神经系统不良反应，并且针对降低IL-6的治疗可能在临床上具有认知益处。
Multiple studies have shown that plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) are elevated in patients with important and prevalent adverse health conditions, including atherosclerosis, diabetes, obesity, obstructive sleep apnea, hypertension, and frailty. Higher plasma levels of IL-6, in turn, increase the risk of many conditions associated with aging including age-related cognitive decline. However, the mechanisms underlying this association between IL-6 and cognitive vulnerability remain unclear. We investigated the role of IL-6 in brain aging in young (4 mo) and aged (24 mo) wild-type C57BL6 and genetically-matched IL-6−/− mice, and determined that IL-6 was necessary and sufficient for increased neuronal expression of the superoxide-producing immune enzyme, NADPH-oxidase, and this was mediated by non-canonical NFκB signaling. Furthermore, superoxide production by NADPH-oxidase was directly responsible for age-related loss of parvalbumin (PV)-expressing GABAergic interneurons, neurons essential for normal information processing, encoding, and retrieval in hippocampus and cortex. Targeted deletion of IL-6 or elimination of superoxide by chronic treatment with a superoxide-dismutase mimetic prevented age-related loss of PV-interneurons and reversed age-related cognitive deficits on three standard tests of spatial learning and recall. Present results indicate that IL-6 mediates age-related loss of critical PV-expressing GABAergic interneurons through increased neuronal NADPH-oxidase-derived superoxide production, and that rescue of these interneurons preserves cognitive performance in aging mice, suggesting that elevated peripheral IL-6 levels may be directly and mechanistically linked to long-lasting cognitive deficits in even normal older individuals. Further, because PV-interneurons are also selectively affected by commonly used anesthetic agents and drugs, our findings imply that IL-6 levels may predict adverse CNS effects in older patients exposed to these compounds through specific derangements in inhibitory interneurons, and that therapies directed at lowering IL-6 may have cognitive benefits clinically.
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DOI：
10.1073/pnas.0712197105
发表时间：
2008-02-19
影响因子：
11.1
作者：
Buxbaum, Joel N.;Ye, Zhengyi;Bartfai, Tamas
通讯作者：
Bartfai, Tamas
影响因子：
7.8
作者：
Ali, Sameh S.;Xiong, Chengjie;Quick, Kevin L.
通讯作者：
Quick, Kevin L.
影响因子：
5.3
作者：
Choi, DK;Pennathur, S;Przedborski, S
通讯作者：
Przedborski, S
影响因子：
3.6
作者：
de Erausquin, GA;Hyrc, K;Dugan, LL
通讯作者：
Dugan, LL
影响因子：
3.5
作者：
Driscoll, I;Hamilton, DA;Sutherland, RJ
通讯作者：
Sutherland, RJ