School of Health Sciences, Purdue University, West Lafayette, IN, 47907, USA.
School of Health Sciences, Purdue University, West Lafayette, IN, 47907, USA.
Neurotoxicology. 2022 Jan;88:44-56. doi: 10.1016/j.neuro.2021.10.011. Epub 2021 Oct 27.
The homeostasis of copper (Cu) in the central nervous system is regulated by the blood-brain barrier and blood-cerebrospinal (CSF) barrier (BCB) in the choroid plexus. While proteins responsible for Cu uptake, release, storage and intracellular trafficking exist in the choroid plexus, the influence of age on Cu clearance from the CSF via the choroid plexus and how Cu transporting proteins contribute to the process are unelucidated. This study was designed to test the hypothesis that the aging process diminishes Cu clearance from the CSF of rats by disrupting Cu transporting proteins in the choroid plexus. Data from ventriculo-cisternal perfusion experiments demonstrated greater Cu radioactivity in the CSF effluents of older rats (18 months) compared to younger (1 month) and adult (2 months) rats, suggesting much slower removal of Cu by the choroid plexus in old animals. Studies utilizing qPCR and immunofluorescence revealed an age-specific expression pattern of Cu transporting proteins in the choroid plexus. Moreover, proteomic analyses unraveled age-specific proteomes in the choroid plexus with distinct pathway differences, particularly associated with extracellular matrix and neurodevelopment between young and old animals. Taken together, these findings support an age-dependent deterioration in CSF Cu clearance, which appears to be associated with altered subcellular distribution of Cu transporting proteins and proteomes in the choroid plexus.
中枢神经系统（CNS）中的铜（Cu）稳态由脉络丛中的血脑屏障（BBB）和血脑脊液（CSF）屏障（BCB）调节。虽然脉络丛中存在负责 Cu 摄取、释放、储存和细胞内转运的蛋白质，但年龄对 CSF 中 Cu 通过脉络丛清除的影响以及 Cu 转运蛋白如何促进该过程尚不清楚。本研究旨在检验以下假设，即衰老过程通过破坏脉络丛中的 Cu 转运蛋白，从而降低 CSF 中 Cu 的清除率。脑室-蛛网膜下腔灌流实验的数据表明，与年轻（1 个月）和成年（2 个月）大鼠相比，老年（18 个月）大鼠 CSF 流出物中的 Cu 放射性更强，这表明老年动物中 Cu 由脉络丛清除的速度明显较慢。利用 qPCR 和免疫荧光的研究揭示了脉络丛中 Cu 转运蛋白的年龄特异性表达模式。此外，蛋白质组学分析揭示了脉络丛中具有特定年龄的蛋白质组，其具有明显的差异途径，特别是与年轻和老年动物之间的细胞外基质和神经发育有关。综上所述，这些发现支持 CSF Cu 清除能力随年龄下降，这似乎与脉络丛中 Cu 转运蛋白和蛋白质组的亚细胞分布改变有关。
