Supplementary Material for: Curcumin Requires Tumor Necrosis Factor α Signaling to Alleviate Cognitive Impairment Elicited by Lipopolysaccharide

A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

认知能力减退是正常衰老进程，以及阿尔茨海默病、帕金森病与亨廷顿病等神经退行性疾病的典型特征。尽管此类疾病的病因学存在差异，但均涉及先天免疫通路（innate immune pathways）的局部激活与相关炎性细胞因子（inflammatory cytokines）的参与。然而，针对神经退行性疾病的抗炎药物（anti-inflammatory agents）临床试验结果均不尽如人意，因此亟需更深入地阐明炎症过程在神经功能障碍中发挥的复杂调控作用。膳食来源的植物化学物质姜黄素（curcumin）具有抗炎、抗氧化及神经保护活性。本研究证实，姜黄素可通过依赖功能性肿瘤坏死因子α受体2（tumor necrosis factor α receptor 2, TNFR2）信号通路的分子机制，缓解先天免疫应答激活所伴随的认知缺陷。在活体实验中，对于缺乏功能性肿瘤坏死因子受体（TNFRs）的小鼠，姜黄素无法发挥其对抗海马依赖型空间记忆损伤、上调脑源性神经营养因子（Brain-Derived Neurotrophic Factor, BDNF）等神经保护通路、降低谷氨酰胺酶（glutaminase）水平，以及调控N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor）表达的作用。体外实验表明，姜黄素可通过依赖TNFR2激活的机制，保护体外培养的神经元免受谷氨酸诱导的兴奋性毒性损伤。本研究结果提示，针对认知衰退的治疗策略若能选择性增强TNFR2信号通路，其临床获益可能优于单纯使用抗炎药物。