IL-6 Mediated Degeneration of Forebrain GABAergic Interneurons and Cognitive Impairment in Aged Mice through Activation of Neuronal NADPH Oxidase

BackgroundMultiple 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.
Methods and FindingsWe 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.
ConclusionsPresent 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.

背景 多项研究证实，在罹患动脉粥样硬化、糖尿病、肥胖症、阻塞性睡眠呼吸暂停、高血压及衰弱症等重要且高发的不良健康状态的患者体内，促炎细胞因子白细胞介素-6（interleukin-6, IL-6）的血浆水平显著升高。血浆IL-6水平升高，进一步会增加多种衰老相关疾病的发病风险，其中包括与年龄相关的认知衰退。然而，IL-6与认知易损性之间的这种关联背后的分子机制仍未阐明。
方法与结果 本研究以年轻（4月龄）与老年（24月龄）野生型C57BL/6小鼠及遗传背景匹配的IL-6基因敲除（IL-6−/−）小鼠为模型，探究IL-6在脑衰老过程中的作用。研究证实，IL-6对于产超氧化物的免疫酶——烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NADPH-oxidase）的神经元表达上调是必需且充分的，且这一过程由非经典核因子κB（NFκB）信号通路介导。此外，NADPH-oxidase介导的超氧化物生成，直接导致了与年龄相关的小白蛋白（parvalbumin, PV）阳性γ-氨基丁酸能中间神经元丢失——这类神经元对于海马体与皮层的正常信息处理、编码及提取至关重要。通过特异性敲除IL-6，或长期使用超氧化物歧化酶（superoxide-dismutase）模拟剂清除超氧化物，均可阻止年龄相关的PV阳性中间神经元丢失，并在三项标准空间学习与记忆测试中逆转老年小鼠的认知功能缺陷。
结论 本研究结果表明，IL-6通过上调神经元烟酰胺腺嘌呤二核苷酸磷酸氧化酶的表达，促进其介导的超氧化物生成，从而介导关键的PV阳性γ-氨基丁酸能中间神经元的年龄相关性丢失；而挽救这类中间神经元可维持衰老小鼠的认知功能，这提示即使在健康老年个体中，外周IL-6水平升高也可能与持久性认知缺陷存在直接的机制性关联。此外，由于PV阳性中间神经元也会受到常用麻醉剂与药物的选择性影响，本研究结果提示，IL-6水平可通过抑制性中间神经元的特定紊乱，预测老年患者暴露于这类化合物时产生的中枢神经系统不良效应；而以降低IL-6水平为靶点的治疗手段，在临床中或可带来认知获益。