Taylor Juliet M, Minter Myles R, Newman Andrew G, Zhang Moses, Adlard Paul A, Crack Peter J
Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
Synaptic Neurobiology Laboratory, Mental Health Research Institute, Melbourne, Victoria, Australia.
Neurobiol Aging. 2014 May;35(5):1012-23. doi: 10.1016/j.neurobiolaging.2013.10.089. Epub 2013 Oct 29.
A neuro-inflammatory response has been implicated in human patients and animal models of Alzheimer's disease (AD). Type-1 interferons are pleiotropic cytokines involved in the initiation and regulation of the pro-inflammatory response; however, their role in AD is unknown. This study investigated the contribution of type-1 IFN signaling in the neuro-inflammatory response to amyloid-beta (Aβ) in vitro and in the APP/PS1 transgenic mouse model of AD. Enzyme-linked immunosorbent assay confirmed a 2-fold increase in IFNα in APP/PS1 brains compared with control brains. Quantitative polymerase chain reaction also identified increased IFNα and IFNβ expression in human pre-frontal cortex from AD patients. In vitro studies in primary neurons demonstrated Aβ-induced type-1 IFN expression preceded that of other classical pro-inflammatory cytokines, IL1-β, and IL-6. Significantly, ablation of type-1 interferon-α receptor 1 expression in BE(2)M17 neuroblastoma cells and primary neurons afforded protection against Aβ-induced toxicity. This study supports a role for type-1 interferons in the pro-inflammatory response and neuronal cell death in AD and suggests that blocking type-1 interferon-α receptor 1 maybe a therapeutic target to limit the disease progression.
神经炎症反应与阿尔茨海默病（AD）的人类患者和动物模型有关。1型干扰素是参与促炎反应启动和调节的多效性细胞因子；然而，它们在AD中的作用尚不清楚。本研究调查了1型干扰素信号在体外以及在AD的APP/PS1转基因小鼠模型中对淀粉样β蛋白（Aβ）神经炎症反应中的作用。酶联免疫吸附测定证实，与对照脑相比，APP/PS1脑内的IFNα增加了2倍。定量聚合酶链反应也确定AD患者的人类前额叶皮质中IFNα和IFNβ表达增加。原代神经元的体外研究表明，Aβ诱导的1型干扰素表达先于其他经典促炎细胞因子IL1-β和IL-6。重要的是，BE(2)M17神经母细胞瘤细胞和原代神经元中1型干扰素-α受体1表达的缺失提供了针对Aβ诱导毒性的保护作用。本研究支持1型干扰素在AD的促炎反应和神经元细胞死亡中的作用，并表明阻断1型干扰素-α受体1可能是限制疾病进展的治疗靶点。
