The Role of Ionizing Radiation in Alzheimer’s Disease

项目描述：本行政补充项目的目标是确定是否 细胞外冷诱导RNA结合蛋白（eCIRP），损伤相关分子模式（DAMP） 在辐射暴露时，小胶质细胞释放这种分子，并导致阿尔茨海默氏症中的tau病理学 疾病（AD）。AD是美国第六大死亡原因，也是最常见的神经退行性疾病 痴呆虽然研究已经将电离辐射暴露与认知功能障碍联系起来，但 放射损伤在AD病因学中的作用尚未得到充分研究。已知eCIRP由 辐射细胞和激活的巨噬细胞，我们的初步研究表明， eCIRP在全身照射（TBI）后升高，增加了TBI可能导致小胶质细胞 在中枢神经系统释放eCIRP事实上，我们发现eCIRP在 AD患者的脑脊液。此外，eCIRP增加tau蛋白磷酸化并上调Cdk 5蛋白表达。 通过eCIRP激活白细胞介素-6受体α（IL-6 R α）/STAT 3通路，抑制p25超活化因子。我们也 结果表明，eCIRP竞争性拮抗剂小肽C23可抑制eCIRP对IL-6 R α/STAT 3的激活 和p25的上调。基于这些新的发现，我们假设电离辐射诱导 在一些实施方案中，神经胶质细胞可以通过刺激小胶质细胞在脑中释放eCIRP，导致病理性tau磷酸化和聚集。 此外，我们进一步假设用C23治疗减弱了辐射诱导的tau蛋白的发展。 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样病理性tau蛋白中的作用。 磷酸化和聚集。最后，我们将进行概念验证研究， 用C23拮抗eCIRP是否减弱TBI后病理性tau磷酸化和聚集。 我们的研究将提供新的关键见解电离辐射的确切作用，在发病机制， 以及未来治疗AD患者的新的潜在治疗策略。

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.