Metabolic mechanisms of cognitive decline in aging and AD mediated by inflammatory PGE2 signaling

炎症性前列腺素E2介导的衰老和AD认知功能减退的代谢机制 项目摘要 衰老的特点是发展适应不良的免疫反应，促进认知能力下降 和阿尔茨海默病（AD）。我们最近发现炎症脂质信使前列腺素E2 前列腺素E2（PGE2）通过其EP2受体发出信号，是年龄相关炎症和认知功能障碍的主要驱动因素。 下降髓系细胞中EP2受体的基因缺失足以防止全身和脑损伤。 炎症和认知能力下降。髓样EP2缺失拯救健康免疫细胞 通过恢复衰老巨噬细胞中的葡萄糖通量和下游线粒体呼吸来响应， 小胶质细胞我们还发现了一个令人惊讶的现象，即非脑组织对EP2信号的外周抑制， 渗透性EP 2拮抗剂表型模仿了全髓系EP 2基因缺失的作用。这些数据表明 外周抑制促炎性PGE2信号足以恢复健康的海马 在衰老的老鼠中发挥作用。在这项提案中，我们将建立在这些初步发现的基础上， 外周中的重编程骨髓细胞可以引起血脑屏障（BBB）以外的作用， 逆转衰老和AD病理模型中海马功能的变化。我们将检验这个假设 EP2抑制对外周骨髓细胞的有益免疫代谢作用被传递， 从血液到脑内皮，然后到星形胶质细胞，导致改善星形胶质细胞对脑血管的支持。 神经元我们将采用衰老和突变APP系的临床前模型，靶向代谢组学， 转录组学，以了解如何改善外周骨髓能量代谢导致有益的影响 超越血脑屏障我们将测试外周EP2免疫阻断，通过重编程 循环血液，将改善内皮功能。然后我们将测试是否星形胶质细胞，其足处理 包封毛细管床的材料在功能上又得到改善。由于星形胶质细胞支持神经元代谢，我们 假设外周EP2抑制将改善神经元星形胶质细胞支持，导致改善的 认知功能的老化和AD模型。

Metabolic mechanisms of cognitive decline in aging and AD mediated by inflammatory PGE2 signaling Project Summary Aging is characterized by the development of maladaptive immune responses that promote cognitive decline and Alzheimer’s disease (AD). We recently identified the inflammatory lipid messenger prostaglandin E2 (PGE2), signaling through its EP2 receptor, as a major driver of age-associated inflammation and cognitive decline. Genetic deletion of the EP2 receptor in myeloid cells was sufficient to prevent systemic and brain inflammation and cognitive decline in aging mice. Myeloid EP2 deletion rescued healthy immune cell responses by restoring glucose flux and downstream mitochondrial respiration in aging macrophages and microglia. We also made the surprising observation that peripheral inhibition of EP2 signaling with a non-brain penetrant EP2 antagonist phenocopied the effect of pan-myeloid EP2 genetic deletion. These data suggest that peripheral inhibition of pro-inflammatory PGE2 signaling is sufficient to restore healthy hippocampal function in aging mice. In this proposal, we will build on these initial findings and define how metabolically reprogrammed myeloid cells in the periphery can elicit effects beyond the blood-brain barrier (BBB) that reverse changes in hippocampal function in models of aging and AD pathology. We will test the hypothesis that the beneficial immune-metabolic effects of EP2 inhibition on myeloid cells in the periphery are transmitted from the blood to the cerebral endothelium and then to astrocytes, leading to improved astrocytic support of neurons. We will employ preclinical models of aging and mutant APP lines, targeted metabolomics and transcriptomics to understand how improving peripheral myeloid energy metabolism leads to beneficial effects beyond the blood brain barrier. We will test whether peripheral EP2 immune blockade, by reprogramming circulating blood, will improve endothelial function. We will then test whether astrocytes, whose foot processes envelop the capillary bed are in turn functionally improved. As astrocytes support neuronal metabolism, we hypothesize that peripheral EP2 inhibition will improve astrocytic support of neurons, leading to improved cognitive function in models of aging and AD.