The Role of Ionizing Radiation in Alzheimer’s Disease

电离辐射在阿尔茨海默病中的作用

• 批准号: 10288222
• 负责人: Max Brenner
• 金额: $ 41.88万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288222
• 关键词: Administrative Supplement; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Antibodies; Attenuated; Brain; Cause of Death; Cells; Cerebrospinal Fluid; Congenic Mice; Development; Dose; Enzyme-Linked Immunosorbent Assay; Etiology; Exposure to; Female; Future; Genome; Goals; Hour; ITGAM gene; Immunoglobulin G; Immunohistochemistry; Impaired cognition; Injections; Injury; Interleukin 6 Receptor; Interleukin Activation; Ionizing radiation; Knock-out; Link; MAPT gene; Measures; Mediator of activation protein; Microglia; Molecular; Mus; Myelogenous; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neurons; Oligopeptides; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Peptides; Phagocytes; Phosphotransferases; Process; RNA-Binding Proteins; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation exposure; Recombinants; Role; STAT3 gene; Saline; Serum; Source; Tauopathies; Therapeutic; Time; Tissues; Transgenic Organisms; Up-Regulation; Whole-Body Irradiation; base; congenic; experimental study; extracellular; inhibitor/antagonist; insight; interleukin-6 receptor alpha; irradiation; macrophage; male; monocyte; mortality; neurodegenerative dementia; novel; polyclonal antibody; public health relevance; systemic inflammatory response; tau Proteins; tau aggregation; tau phosphorylation; tau-1; tissue injury

PROJECT DESCRIPTION: The goal of this Administrative Supplement project is to determine whether extracellular cold inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern (DAMP) molecule, is released by microglial cells upon radiation exposure and leads to tau pathology in Alzheimer’s disease (AD). AD is the 6th leading cause of death in the US and the most common form of neurodegenerative dementia. Although studies have linked ionizing radiation exposure to cognitive dysfunction, the role of radiation injury in the etiology of AD has not been sufficiently explored. eCIRP is known to be released by irradiated cells and activated macrophages, and our preliminary studies have shown that serum levels of eCIRP are elevated after total body irradiation (TBI), raising the possibility that TBI may cause microglial cells to release eCIRP in the central nervous system. Indeed, we discovered that eCIRP was increased in the cerebrospinal fluid of AD patients. Moreover, eCIRP increased tau phosphorylation and upregulated the Cdk5 hyperactivator p25 via eCIRP’s activation of the interleukin-6 receptor α (IL-6Rα)/STAT3 pathway. We also showed that the eCIRP competitive antagonist small peptide C23 inhibited eCIRP’s activation of IL-6Rα/STAT3 and upregulation of p25. Based on these novel findings, we hypothesize that ionizing radiation induces microglial cells to release eCIRP in the brain, leading to pathological tau phosphorylation and aggregation. Moreover, we further hypothesize that treatment with C23 attenuates the development of radiation-induced tau pathology. In this project, we plan to determine the effects of irradiation and the contribution of microglial cells to brain eCIRP release. We will then demonstrate the role of eCIRP in the induction of AD-like pathological tau phosphorylation and aggregation after irradiation. Finally, we will conduct a proof-of-concept study to evaluate whether eCIRP antagonism with C23 attenuates pathological tau phosphorylation and aggregation after TBI. Our studies will provide novel pivotal insights into the precise role of ionizing radiation in the pathogenesis of AD, as well as new potential therapeutic strategies for treating AD patients in the future.

项目描述：此行政补充项目的目的是确定是否是否 细胞外冷诱导RNA结合蛋白（ECIRP），一种与损伤相关的分子模式（湿） 分子在辐射暴露后通过小胶质细胞释放，并导致阿尔茨海默氏症的tau病理 疾病（AD）。 AD是美国的第六个主要死亡原因，也是最常见的神经退行性形式 失智。尽管研究已将电离辐射暴露与认知功能障碍联系起来，但 AD病因中的辐射损伤尚未得到充分探索。 ECIRP已知由 辐照细胞和活化的巨噬细胞，我们的初步研究表明血清水平 全身照射（TBI）后ECIRP升高，增加了TBI可能引起小胶质细胞的可能性 在中枢神经系统中释放ECIRP。确实，我们发现ECIRP在 AD患者的脑脊液。此外，ECIRP增加了tau磷酸化并更新了CDK5 通过ECIRP激活白介素-6受体α（IL-6Rα）/STAT3途径的过度激活p25。我们也是 表明ECIRP竞争性拮抗剂小肽C23抑制了ECIRP的激活IL-6Rα/STAT3 和p25的上调。基于这些新颖的发现，我们假设电离辐射会影响 小胶质细胞在大脑中释放ECIRP，从而导致病理tau磷酸化和聚集。 此外，我们进一步假设用C23的治疗减弱了辐射引起的TAU的发展 病理。在这个项目中，我们计划确定辐射的影响和小胶质细胞的贡献 大脑ECIRP释放。然后，我们将证明ECIRP在诱导AD样病理TAU中的作用 照射后的磷酸化和聚集。最后，我们将进行概念验证研究以评估 ECIRP与C23的拮抗作用是否减弱了TBI后病理Tau磷酸化和聚集。 我们的研究将为电离辐射在发病机理中的精确作用提供新的关键见解 AD以及将来治疗AD患者的新潜在治疗策略。