AD小鼠脑胶质淋巴系统CSF流入量与年龄的关系:基于9.4 T DCE-MRI的可视化研究  

Relationship between CSF inflow into the cerebral glymphatic system of AD mice and age:A visualization study based on 9.4 T DCE-MRI

作　　者：江心雨 苏云燕 胡春洪[1] 张龙江[2] JIANG Xinyu;SU Yunyan;HU Chunhong;ZHANG Longjiang(Department of Radiology,the First Affiliated Hospital of Soochow University,Suzhou 215008,China;Department of Medical Imaging,Jinling Hospital,Medical School of Nanjing University,Nanjing 210002,China)

机构地区：[1]苏州大学附属第一医院放射科,苏州215008 [2]南京大学医学院金陵医院医学影像科,南京210002

出　　处：《磁共振成像》2024年第4期113-119,共7页Chinese Journal of Magnetic Resonance Imaging

基　　金：江苏省重点医学学科项目(编号:JSDW202242);江苏省青年科技人才托举工程项目(编号:TJ-2023-028)。

摘　　要：目的基于9.4 T动态对比增强(dynamic contrast-enhanced,DCE)-MRI探索不同月龄的阿尔茨海默病(Alzheimer's disease,AD)模型小鼠脑胶质淋巴系统的脑脊液(cerebrospinal fluid,CSF)流入变化,以阐明随年龄增长脑胶质淋巴系统清除的变化规律及水通道蛋白4(aquaporin4,AQP4)在脑胶质淋巴系统清除中的作用。材料与方法取2、4、6和8月龄的APP/PS1 AD小鼠和野生型(wild-type,WT)小鼠,每组1只,共8组,向小脑延髓池中注射钆喷酸葡胺(Gadopentetate dimeglumine,Gd-DTPA)后第30 min完成第一次DCE-MRI扫描,以后每15 min采集一次,共完成8次扫描。随后在DCE-MRI扫描之前,使用AQP4抑制剂N-(1,3,4-噻二唑基)烟酰胺[N-(1,3,4-Thiadiazolyl)nicotinamide,TGN-020]对2月龄WT小鼠进行处理。采用免疫荧光法检测AQP4和β-淀粉样蛋白随月龄增长的表达变化。结果在APP/PS1小鼠模型的疾病早期,观察到随月龄增加,淀粉样蛋白逐渐累积,CSF流入信号强度均值从增加到降低,其中4至6月龄小鼠淀粉样蛋白的累积速率缓慢,对应于相应月龄CSF流入信号强度均值最高(4月龄为2711.67±1270.25;6月龄为2632.25±729.65)。同时,AQP4表现出随月龄增加极化程度降低的变化过程。随后,经AQP4抑制剂TGN-020处理后,观察到脑胶质淋巴系统的CSF流入信号强度均值降低(由3578.08±1199.95下降为1655.42±377.96;P=0.06)。结论在AD疾病的早期阶段(8月龄前),6月龄的脑胶质淋巴系统利用更明显,此阶段可能作为AD治疗的窗口期。AQP4在脑胶质淋巴系统中起着重要作用,可能作为研究和治疗AD的靶点。Objective:To explore the changes of cerebrospinal fluid(CSF)inflow into the cerebral glymphatic system(GS)in Alzheimer's disease(AD)model mice at different ages via 9.4 T dynamic contrast-enhanced(DCE)-MRI,in order to elucidate the alterations through the cerebral GS clearance with age,and the role of aquaporin 4(AQP4)in the cerebral GS clearance.Materials and Methods:APP/PS1 AD mice and wild-type(WT)mice aged 2,4,6,and 8 months were included in a total of 8 groups,with 1 mouse in each group.After injection of gadolinium contrast agent Gadopentate dimeglumine(Gd-DTPA)into the cerebellomedullary cistern,the first DCE-MRI scan was completed at 30 minutes,followed by collection every 15 minutes until a total of 8 imaging scans were completed.Subsequently,AQP4 inhibitor N-(1,3,4-thiadiazole)nicotinamide(TGN-020)was used to treat WT mice aged 2 months before DCE scanning.Immunofluorescence assay was used to detect the expression changes of AQP4 andβ-amyloid protein with increasing age.Results:In the early stage of AD of the APP/PS1 mouse model,it was observed that with increasing age,amyloid protein gradually accumulated,and mean signal intensity of CSF inflow showed an initial increase followed by a decrease.At 4 to 6 months of age,the deposition rate ofβ-amyloid protein was slow,corresponding to the highest mean signal intensity of CSF inflow at corresponding age(CSF inflow at 4 months old,2711.67±1270.25;CSF inflow at 6 months old,2632.25±729.65).Meanwhile,AQP4 exhibited a decreasing polarization degree with increasing age.Subsequently,after treatment with AQP4 inhibitor TGN-020,a decrease in mean signal intensity of CSF inflow was observed in the GS(from 3578.08±1199.95 to 1655.42±377.96;P=0.06).Conclusions:In the early stage of AD disease(before 8 months of age),the utilization of the cerebral GS is more pronounced in 6-month-old mice,which may serve as a window period for AD treatment.AQP4 plays an important role in the cerebral GS and may be a breakthrough point for studying and treating AD.

关 键 词：脑胶质淋巴系统 阿尔茨海默病 9.4 T磁共振成像 动态对比增强磁共振成像 水通道蛋白4 APP/PS1小鼠 

分 类 号：R445.2[医药卫生—影像医学与核医学] R-332[医药卫生—诊断学]