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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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 信号介导的衰老和 AD 认知能力下降的代谢机制项目概要衰老的特点是适应不良的免疫反应的发展，从而促进认知能力下降我们最近发现了炎症脂质信使前列腺素 E2。 (PGE2)，通过其 EP2 受体发出信号，是与年龄相关的炎症和认知的主要驱动因素骨髓细胞中 EP2 受体的基因缺失足以预防全身和大脑的衰退。衰老小鼠的炎症和认知能力下降挽救了健康的免疫细胞。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做出反应我们还做出了令人惊讶的观察，即非脑外周神经元对 EP2 信号传导的抑制。渗透性 EP2 拮抗剂表型复制了全髓系 EP2 基因缺失的影响。促炎 PGE2 信号传导的外周抑制足以恢复健康的海马在本提案中，我们将在这些初步发现的基础上定义代谢的机制。外周粒细胞重新编程可以引发血脑屏障（BBB）之外的效应逆转衰老和 AD 病理模型中海马功能的变化我们将检验这一假设。 EP2 抑制对外周骨髓细胞的有益免疫代谢作用可以传递从血液到脑内皮，然后到星形胶质细胞，从而改善星形胶质细胞的支持我们将采用衰老和突变 APP 系的临床前模型、靶向代谢组学和转录组学以了解改善外周骨髓能量代谢如何产生有益效果我们将通过重编程来测试外周EP2免疫是否被阻断。然后，我们将测试足突的星形胶质细胞是否会改善内皮功能。由于星形胶质细胞支持神经元代谢，因此包围毛细血管床的功能也得到改善。研究表明，外周 EP2 抑制将改善神经元的星形胶质细胞支持，从而改善衰老和 AD 模型中的认知功能。