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

炎症 PGE2 信号介导的衰老和 AD 认知能力下降的代谢机制

• 批准号: 10590390
• 负责人: Katrin I. Andreasson
• 金额: $ 192.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590390
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Astrocytes; Bioenergetics; Biological; Blood; Blood - brain barrier anatomy; Brain; Cell Reprogramming; Cells; Cerebrovascular system; Cerebrum; Data; Development; Dinoprostone; Encephalitis; Endothelium; Energy Metabolism; Foot Process; Genetic; Genetic Transcription; Glucose; Hippocampus; Human; Immune; Immune Plasma; Immune response; Immunologic Factors; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Investigation; Link; Lipids; Macrophage; Mediating; Memory; Metabolic; Metabolism; Microglia; Mitochondria; Modeling; Mus; Myelogenous; Myeloid Cells; Neurons; Organ; Outcome; Pathway interactions; Pericytes; Peripheral; Phenocopy; Pre-Clinical Model; Rejuvenation; Research; Respiration; RiboTag; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transcript; aged; antagonist; blood-brain barrier function; brain endothelial cell; capillary bed; cognitive function; functional improvement; immune function; improved; in vivo; metabolomics; monocyte; mouse model; mutant; neuronal metabolism; pre-clinical; prevent; receptor; response; systemic inflammatory response; transcriptomics; translational study; transmission process

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.

炎症PGE2信号传导介导的认知下降和AD的代谢机制 项目摘要 衰老的特征是发展适应不良免疫的发展，促进认知能力下降 和阿尔茨海默氏病（AD）。我们最近确定了炎症性脂质信使前列腺素E2 （PGE2），通过其EP2受体发出信号，是年龄相关感染和认知的主要驱动力 衰退。髓样细胞中EP2受体的遗传缺失足以防止全身和脑 衰老小鼠的炎症和认知能力下降。髓样EP2缺失救出了健康的免疫细胞 通过恢复老化巨噬细胞中的葡萄糖通量和下游线粒体呼吸的反应 小胶质细胞。我们还做出了令人惊讶的观察结果，即对非脑的外周抑制EP2信号传导 渗透剂EP2拮抗剂表现了泛乳细胞EP2遗传缺失的作用。这些数据暗示 促炎性PGE2信号的外围抑制足以恢复健康的海马 衰老小鼠的功能。在此提案中，我们将基于这些初始发现，并定义如何代谢 重新编程的外周中的髓样细胞可以引起血脑屏障（BBB）以外的影响 在衰老和AD病理模型中，海马功能的反向变化。我们将检验假设 EP2抑制对周围髓样细胞的有益免疫代谢作用是传播的 从血液到大脑内皮，然后再到星形胶质细胞，从而改善了星形胶质细胞的支持 神经元。我们将采用衰老和突变应用程序线，有针对性的代谢组学以及的临床前模型 转录组学了解如何改善外周髓能量代谢会导致有益的影响 超越血脑屏障。我们将通过重新编程测试外围EP2免疫阻滞 循环血液，将改善内皮功能。然后，我们将测试星形胶质细胞的脚步 毛细管床的包裹又在功能上得到了改善。当星形胶质细胞支持神经元代谢时，我们 假设外周EP2抑制作用将改善神经元的星形细胞支持，从而改善 衰老和AD模型中的认知功能。