Carrano Anna, Das Pritam
Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, United States of America.
PLoS One. 2015 Oct 8;10(10):e0140210. doi: 10.1371/journal.pone.0140210. eCollection 2015.
Amyloid precursor protein (APP) and its cleaved products have been reported to have important functions in CNS health, including in memory and synapse formation, cell survival and neuroprotection. Furthermore APP and its cleaved products have been shown to be transiently increased in response to various CNS stressors, suggesting a role in response to acute cellular injury. In an attempt to further understand the function of APP in response to CNS injury, we have used intracranial LPS injection as an inflammatory injury model in APP knock out mice (APPKO). Our data show that innate immune responses to LPS injection is significantly blunted in APPKO mice compared to APP sufficient wild type (BL6) mice. Morphologically, glial cells in APPKO mice appear less reactive, with shorter ramified processes and smaller cell bodies in response to LPS. Additionally, quantitative RT-PCR analysis for several glia markers and innate immune cytokine levels (e.g. TNFα, IL-6, IL-1β and IL-10) showed significantly reduced expression levels in LPS injected APPKO mice. In vitro cell culture assays confirmed this attenuated response to LPS stimulation by primary microglial cells isolated from APPKO mice. Our data suggests that APP full length protein and/or its cleaved products are necessary to mount a complete and effective innate immune cell response to inflammatory injury.
淀粉样前体蛋白（APP）及其裂解产物据报道在中枢神经系统健康中具有重要功能，包括在记忆和突触形成、细胞存活及神经保护方面。此外，APP及其裂解产物已被证明会因各种中枢神经系统应激源而短暂增加，这表明其在应对急性细胞损伤中发挥作用。为了进一步了解APP在应对中枢神经系统损伤时的功能，我们在APP基因敲除小鼠（APPKO）中使用颅内注射脂多糖作为炎症损伤模型。我们的数据表明，与APP充足的野生型（BL6）小鼠相比，APPKO小鼠对脂多糖注射的固有免疫反应明显减弱。形态学上，APPKO小鼠的胶质细胞反应性较低，对脂多糖的反应是分支较短且细胞体较小。此外，对几种胶质细胞标志物和固有免疫细胞因子水平（如TNFα、IL-6、IL-1β和IL-10）的定量RT-PCR分析显示，注射脂多糖的APPKO小鼠中这些因子的表达水平显著降低。体外细胞培养试验证实了从APPKO小鼠分离的原代小胶质细胞对脂多糖刺激的反应减弱。我们的数据表明，APP全长蛋白和/或其裂解产物是对炎症损伤产生完整且有效的固有免疫细胞反应所必需的。
