Regulation of Microglial Activation State by a Lipid Transporter

摘要 全基因组功能关联研究表明，小胶质细胞激活异常 是阿尔茨海默病患者神经退行性变和认知能力下降的主要因素 (Ad)。因此，调节小胶质细胞的激活状态可能具有深刻的治疗潜力 广告。然而，小胶质细胞在不同状态之间转换的潜在机制 在正常和疾病期间，情况在很大程度上是未知的。S1P-信号已被牵连到 在AD中扮演着重要的角色。然而，由于相互矛盾的报道，S1P在AD中的作用尚不清楚。 一方面，死后AD患者大脑中S1P水平降低，表明 S1P的保护作用。另一方面，也有报告表明，S1P可能会发挥作用 恰恰相反。虽然已经在β相关的AD小鼠模型上进行了测试，但FTY720在 牛磺酸的病理难以捉摸。此外，FTY720可以根据细胞的不同而具有不同的功能 背景和治疗程序，这使得对S1P的作用的解释具有挑战性。因此， S1P信号在阿尔茨海默病中的作用比人们想象的要复杂得多，需要进一步研究 我们的初步研究表明，Spinster Homolog 2(Spns2)，一种S1P转运体，对 调节小胶质细胞从炎症状态向抗炎状态的转变 一种β多肽。这个数据很有趣，因为它揭示了小胶质细胞的状态可以通过 Spns2和/或S1P。由于小胶质细胞是中枢神经系统免疫防御的第一道主线。 神经系统，我们将主要研究Spns2在小胶质细胞激活中的作用。 申请。星形胶质细胞，另一种主要的胶质细胞类型，以及其他S1P转运体的作用 作为ABCA1，也将进行评估。我们的目标是定义功能和潜在的机制 Spns2在AD小胶质细胞反应中的表达。我们的目标是定义功能和基础 Spns2在AD小胶质细胞反应中的作用机制我们的首要假设是Spns2 促进小胶质细胞促炎活性参与AD发病机制 广告相关的刺激。我们将测试(1)Spns2增强小胶质细胞的促炎反应 在AD相关刺激诱导下，(2)Spns2/S1P促进NFκB和p38MAPK促炎 Aβ和tau诱导的小胶质细胞信号转导；(3)Spns2缺乏改善AD相关 小鼠阿尔茨海默病模型的表型。通过将重点放在S1P转运体Spns2上，该提议成立 这是揭示S1P信号在AD发病机制中新方面的独特前提。

Abstract Functional genome wide association studies have indicated that dysregulated microglia activation is a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease (AD). Thus, regulating the microglia activation state could have profound therapeutic potential for AD. However, the underlying mechanisms by which microglia transition between different states during normal and disease conditions are largely unknown. S1P-signaling has been implicated to play important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports. On one hand, the level of S1P is reduced in postmortem AD patient brains, suggesting a protective role of S1P. On the other hand, there are also reports indicating that S1P might play the opposite. Although has been tested in Aβ-related AD mouse models, the role of FTY720 in tau pathology is elusive. Further, FTY720 can have different function depending on the cellular context and treatment procedure, which makes interpretation of S1P's role challenging. Thus, the function of S1P-signaling in AD is more complex than assumed and demands further investigation Our preliminary studies suggest that Spinster homolog 2 (Spns2), an S1P transporter, critically modulates microglial transition from inflammatory to anti-inflammatory states when treated with Aβ peptide. This data is interesting in that it reveals microglia states could be regulated through Spns2 and/or S1P. Since microglia form the first and major line of immune defense in the central nervous system, we will mainly investigate the function of Spns2 on microglia activation in this application. The role of astrocytes, the other major glial cell type, and other S1P transporters such as ABCA1, will also be evaluated. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2 contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microglia induced by AD-related stimuli, (2) Spns2/S1P promotes NFκB and p38 MAPK pro-inflammatory signaling induced by Aβ and tau in microglia, and (3) Spns2 deficiency ameliorates AD-related phenotypes in murine AD models. By focusing on the S1P transporter Spns2, this proposal holds a unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.