Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
J Neuroimmune Pharmacol. 2017 Dec;12(4):670-681. doi: 10.1007/s11481-017-9753-6. Epub 2017 Jun 15.
It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD. Transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) and their littermates were/were not infected with Bordetella pertussis and were treated orally with FTY720 or vehicle beginning 3 days before infection. Infection increased astrocytic activation and enhanced blood brain barrier (BBB) permeability and these changes were attenuated in FTY720-treated B. pertussis-infected mice. Significantly, infection increased Aβ containing plaques and soluble Aβ and these infection-related changes were also attenuated in FTY720-treated B. pertussis-infected mice. The data suggest that this effect results from an FTY720-induced increase in Aβ phagocytosis by astrocytes. FTY720 did not impact on genotype-related changes in the absence of an infection indicating that its potential usefulness is restricted to reducing the impact of acute inflammatory stimuli in AD.
众所周知，感染对阿尔茨海默病（AD）患者有显著的不利影响，加速认知能力下降，甚至在健康衰老个体中，增加大脑中的淀粉样蛋白-β（Aβ）积累。在 AD 的动物模型中感染也会造成损害，有证据表明神经炎症增加、淀粉样蛋白病理学和认知功能恶化。这些变化发生在感染的易感性随着年龄和 AD 相关增加的背景下。在这里，我们着手确定 FTY720 是否可以调节 AD 动物模型中的感染影响，FTY720 是一种与神经鞘氨醇-1-磷酸（S1P）受体结合的分子，具有已知的免疫抑制作用，介导其在多发性硬化症（MS）中的治疗作用。过表达淀粉样前体蛋白（APP）和早老素 1（PS1；APP/PS1 小鼠）的转基因小鼠及其同窝仔鼠被/未感染百日咳博德特氏菌，并在感染前 3 天开始用 FTY720 或载体口服治疗。感染增加了星形胶质细胞的激活并增强了血脑屏障（BBB）通透性，这些变化在 FTY720 处理的百日咳博德特氏菌感染小鼠中减弱。值得注意的是，感染增加了含有 Aβ的斑块和可溶性 Aβ，这些与感染相关的变化在 FTY720 处理的百日咳博德特氏菌感染小鼠中也减弱了。数据表明，这种效应是由于 FTY720 诱导星形胶质细胞增加了对 Aβ的吞噬作用。在没有感染的情况下，FTY720 没有影响与基因型相关的变化，这表明其潜在的有用性仅限于减轻 AD 中急性炎症刺激的影响。
