The Role of Ionizing Radiation in Alzheimer’s Disease

项目描述：该行政副刊项目的目标是确定是否 细胞外冷诱导RNA结合蛋白(ECIRP)，一种损伤相关的分子模式(DAMP) 分子，由小胶质细胞在辐射暴露时释放，并导致阿尔茨海默病的tau病理 疾病(AD)。AD是美国第六大死因，也是最常见的神经退行性疾病 痴呆症。尽管研究已经将电离辐射暴露与认知功能障碍联系在一起，但 辐射损伤在阿尔茨海默病发病机制中的作用尚未得到充分的研究。已知eCIRP由以下公司发布 辐射细胞和激活的巨噬细胞，我们的初步研究表明，血清中 全身照射后eCIRP升高，增加了全身照射后引起小胶质细胞的可能性 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的磷酸化，上调cdk5的表达。 ECIRP通过激活白细胞介素6受体α(IL-6Rα)/STAT3途径激活超激活剂p25。我们也 ECIRP竞争性拮抗剂C23抑制ECIRP对IL-6Rα/STAT3的激活 P25的表达上调。基于这些新的发现，我们假设电离辐射会引起 小胶质细胞在脑内释放eCIRP，导致病理性tau的磷酸化和聚集。 此外，我们进一步假设，用C23治疗可以延缓辐射诱导的tau的发展。 病理学。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。 脑部eCIRP释放。然后，我们将演示eCIRP在诱导AD样病理性tau中的作用 辐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 C23拮抗eCIRP是否减轻脑损伤后病理性tau的磷酸化和聚集。 我们的研究将为电离辐射在糖尿病发病机制中的确切作用提供新的关键见解。 AD，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.