Share：
Share this content in WeChat
X
[Chinese][PDF]1313
• Original Article •
Relationship between CSF inflow into the cerebral glymphatic system of AD mice and age: A visualization study based on 9.4 T DCE-MRI
JIANG Xinyu  SU Yunyan  HU Chunhong  ZHANG Longjiang 

Cite this article as: JIANG X Y, SU Y Y, HU C H, et al. Relationship between CSF inflow into the cerebral glymphatic system of AD mice and age: A visualization study based on 9.4 T DCE-MRI[J]. Chin J Magn Reson Imaging, 2024, 15(4): 113-119. DOI:10.12015/issn.1674-8034.2024.04.018.


[Abstract] 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 and β-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 of β-amyloid protein was slow, corresponding to the highest mean signal intensity of CSF inflow at corresponding age (CSF inflow at 4 months old, 2 711.67±1 270.25; CSF inflow at 6 months old, 2 632.25±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 3 578.08±1 199.95 to 1 655.42±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.
[Keywords] cerebral glymphatic system；Alzheimer's disease；9.4 T magnetic resonance imaging；dynamic contrast-enhanced magnetic resonance imaging；aquaporin 4 (AQP4)；APP/PS1 mouse model

JIANG Xinyu1   SU Yunyan1   HU Chunhong1*   ZHANG Longjiang2  

1 Department of Radiology, the First Affiliated Hospital of Soochow University, Suzhou 215008, China

2 Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China

Corresponding author: HU C H, E-mail: hch5305@163.com

Conflicts of interest   None.

Received  2023-12-29
Accepted  2024-03-29
DOI: 10.12015/issn.1674-8034.2024.04.018
Cite this article as: JIANG X Y, SU Y Y, HU C H, et al. Relationship between CSF inflow into the cerebral glymphatic system of AD mice and age: A visualization study based on 9.4 T DCE-MRI[J]. Chin J Magn Reson Imaging, 2024, 15(4): 113-119. DOI:10.12015/issn.1674-8034.2024.04.018.

[1]
CHANG Y L, YANG C C, HUANG Y Y, et al. The HSP40 family chaperone isoform DNAJB6b prevents neuronal cells from tau aggregation[J/OL]. BMC Biol, 2023, 21(1): 293 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/38110916/. DOI: 10.1186/s12915-023-01798-6.
[2]
VICENTE-ZURDO D, ROSALES-CONRADO N, LEON-GONZALEZ M E. Unravelling the in vitro and in vivo potential of selenium nanoparticles in Alzheimer's disease: A bioanalytical review[J/OL]. Talanta, 2023, 269: 125519 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/38086100/. DOI: 10.1016/j.talanta.2023.125519.
[3]
CHEN X Y, FIRULYOVA M, MANIS M, et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy[J]. Nature, 2023, 615(7953): 668-677. DOI: 10.1038/s41586-023-05788-0.
[4]
LIU Y, DING R, XU Z, et al. Roles and Mechanisms of the Protein Quality Control System in Alzheimer's Disease[J/OL]. Int J Mol Sci, 2021, 23(1) [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/35008771/. DOI: 10.3390/ijms23010345.
[5]
DO H A, BAEK K H. Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases[J/OL]. Ageing Res Rev, 2021, 69:101367 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/34023421/. DOI: 10.1016/j.arr.2021.101367.
[6]
SWEENEY M D, ZHAO Z, MONTAGNE A, et al. Blood-brain barrier: from physiology to disease and back[J]. Physiol Rev, 2019, 99(1): 21-78. DOI: 10.1152/physrev.00050.2017.
[7]
UCHIDA Y, KAN H, SAKURAI K, et al. Contributions of blood-brain barrier imaging to neurovascular unit pathophysiology of Alzheimer's disease and related dementias[J/OL]. Front Aging Neurosci, 2023, 15: 1111448 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/36861122/. DOI: 10.3389/fnagi.2023.1111448.
[8]
VERHEGGEN I C M, VAN BOXTEL M P J, VERHEY F R J, et al. Interaction between blood-brain barrier and glymphatic system in solute clearance[J/OL]. Neurosci Biobehav Rev, 2018, 90: 26-33 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/29608988/. DOI: 10.1016/j.neubiorev.2018.03.028.
[9]
RASMUSSEN M K, MESTRE H, NEDERGAARD M. Fluid transport in the brain[J]. Physiol Rev, 2022, 102(2): 1025-1151. DOI: 10.1152/physrev.00031.2020.
[10]
GOULAY R, MENA ROMO L, HOL E M, et al. From stroke to dementia: a comprehensive review exposing tight interactions between stroke and amyloid-β formation[J]. Transl Stroke Res, 2020, 11(4): 601-614. DOI: 10.1007/s12975-019-00755-2.
[11]
HAMILTON M G. Editorial. The glymphatic system imagined and now imaged: what is it, and why is it important[J/OL]? J Neurosurg, 2023: 1-3 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37724797/. DOI: 10.3171/2023.7.JNS231284.
[12]
HARRISON I F, ISMAIL O, MACHHADA A, et al. Impaired glymphatic function and clearance of tau in an Alzheimer's disease model[J]. Brain, 2020, 143(8): 2576-2593. DOI: 10.1093/brain/awaa179.
[13]
SILVA I, SILVA J, FERREIRA R, et al. Glymphatic system, AQP4, and their implications in Alzheimer's disease[J/OL]. Neurol Res Pract, 2021, 3(1): 5 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/33499944/. DOI: 10.1186/s42466-021-00102-7.
[14]
GOMOLKA R S, HABLITZ L M, MESTRE H, et al. Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation[J/OL]. Elife, 2023, 12 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/36757363/. DOI: 10.7554/eLife.82232.
[15]
LIU Y, HU P P, ZHAI S, et al. Aquaporin 4 deficiency eliminates the beneficial effects of voluntary exercise in a mouse model of Alzheimer's disease[J]. Neural Regen Res, 2022, 17(9): 2079-2088. DOI: 10.4103/1673-5374.335169.
[16]
ZAMANI A, WALKER A K, ROLLO B, et al. Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis[J/OL]. Transl Neurodegener, 2022, 11(1): 17 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/35287738/. DOI: 10.1186/s40035-022-00291-4.
[17]
BEN-NEJMA I R H, KELIRIS A J, VANREUSEL V, et al. Altered dynamics of glymphatic flow in a mature-onset Tet-off APP mouse model of amyloidosis[J/OL]. Alzheimers Res Ther, 2023, 15(1): 23 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/36707887/. DOI: 10.1186/s13195-023-01175-z.
[18]
CRATER S, MAHARJAN S, QI Y, et al. Resolution and b value dependent structural connectome in ex vivo mouse brain[J/OL]. Neuroimage, 2022, 255: 119199 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/35417754/. DOI: 10.1016/j.neuroimage.2022.119199.
[19]
HUANG Q, JIANG C, XIA X, et al. Pathological BBB Crossing Melanin-Like Nanoparticles as Metal-Ion Chelators and Neuroinflammation Regulators against Alzheimer's Disease[J/OL]. Research (Wash D C), 2023, 6: 0180 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37363131/. DOI: 10.34133/research.0180.
[20]
XAVIER A L R, HAUGLUND N L, VON HOLSTEIN-RATHLOU S, et al. Cannula Implantation into the Cisterna Magna of Rodents[J/OL]. J Vis Exp, 2018(135) [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/29889209/. DOI: 10.3791/57378.
[21]
DING B, LIN C, LIU Q, et al. Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-kappaB signaling pathway in vivo and in vitro[J/OL]. J Neuroinflammation, 2020, 17(1): 302 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/33054814/. DOI: 10.1186/s12974-020-01981-4.
[22]
ANCKAERTS C, BLOCKX I, SUMMER P, et al. Early functional connectivity deficits and progressive microstructural alterations in the TgF344-AD rat model of Alzheimer's Disease: A longitudinal MRI study[J/OL]. Neurobiol Dis, 2019, 124: 93-107 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/30445024/. DOI: 10.1016/j.nbd.2018.11.010.
[23]
KIM SH, AHN JH, YANG H, et al. Cerebral amyloid angiopathy aggravates perivascularclearance impairment in an Alzheimer's disease mouse model[J/OL]. Acta Neuropathol Commun, 2020, 8(1): 181 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/33153499/. DOI: 10.1186/s40478-020-01042-0.
[24]
GAN Y, HOLSTEIN-RONSBO S, NEDERGAARD M, et al. Perivascular pumping of cerebrospinal fluid in the brain with a valve mechanism[J/OL]. J R Soc Interface, 2023, 20(206): 20230288 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37727070/. DOI: 10.1098/rsif.2023.0288.
[25]
YE D, CHEN S, LIU Y, et al. Mechanically manipulating glymphatic transport by ultrasound combined with microbubbles[J/OL]. Proc Natl Acad Sci U S A, 2023, 120(21): e2212933120 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37186852/. DOI: 10.1073/pnas.2212933120.
[26]
WEN Q, TONG Y, ZHOU X, et al. Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)[J/OL]. Neuroimage, 2022, 260: 119464 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/35835339/. DOI: 10.1016/j.neuroimage.2022.119464.
[27]
MATHIISEN T M, LEHRE K P, DANBOLT N C, et al. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction[J]. Glia, 2010, 58(9): 1094-1103. DOI: 10.1002/glia.20990.
[28]
PETERS M E, LYKETSOS C G. The glymphatic system's role in traumatic brain injury-related neurodegeneration[J]. Mol Psychiatry, 2023, 28(7): 2707-2715. DOI: 10.1038/s41380-023-02070-7.
[29]
JI C, YU X, XU W, et al. The role of glymphatic system in the cerebral edema formation after ischemic stroke[J/OL]. Exp Neurol, 2021, 340: 113685 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/33676917/. DOI: 10.1016/j.expneurol.2021.113685.
[30]
GAO Y, LIU K, ZHU J. Glymphatic system: an emerging therapeutic approach for neurological disorders[J/OL]. Front Mol Neurosci, 2023, 16: 1138769 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37485040/. DOI: 10.3389/fnmol.2023.1138769.
[31]
VERKMAN A S, TRADTRANTIP L, SMITH A J, et al. Aquaporin water channels and Hydrocephalus[J]. Pediatr Neurosurg, 2017, 52(6): 409-416. DOI: 10.1159/000452168.
[32]
MESTRE H, HABLITZ LM, XAVIER AL, et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain[J/OL]. Elife, 2018, 7 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/30561329/. DOI: 10.7554/eLife.40070.
[33]
ROSU G C, CATALIN B, BALSEANU T A, et al. Inhibition of aquaporin 4 decreases amyloid Aβ40 drainage around cerebral vessels[J]. Mol Neurobiol, 2020, 57(11): 4720-4734. DOI: 10.1007/s12035-020-02044-8.
[34]
FENG S, WU C Y, ZOU P B, et al. High-intensity interval training ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization[J]. Theranostics, 2023, 13(10): 3434-3450. DOI: 10.7150/thno.81951.
[35]
WU C, ZHANG Q, FENG Y W, et al. GABA promotes interstitial fluid clearance in an AQP4-dependent manner by activating the GABAA R[J]. J Neurochem, 2023, 166(3): 560-571. DOI: 10.1111/jnc.15869.
[36]
WEN G, ZHAN X, XU X, et al. Ketamine Improves the Glymphatic Pathway by Reducing the Pyroptosis of Hippocampal Astrocytes in the Chronic Unpredictable Mild Stress Model[J/OL]. Mol Neurobiol, 2023 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37840071/. DOI: 10.1007/s12035-023-03669-1.
[37]
VERKHRATSKY A, SEMYANOV A. Astrocytes in Ageing[J/OL]. Subcell Biochem, 2023, 103: 253-277 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/37120471/. DOI: 10.1007/978-3-031-26576-1_11.
[38]
LIU S, LI H, SHEN Y, et al. Moxibustion improves hypothalamus Aqp4 polarization in APP/PS1 mice: Evidence from spatial transcriptomics[J/OL]. Front Aging Neurosci, 2023, 15: 1069155 [2023-12-24]. https://pubmed.ncbi.nlm.nih.gov/36819717/. DOI: 10.3389/fnagi.2023.1069155.

PREV Experimental MRI study of targeting Rho-associated protein kinase 1 to detect plaques in atherosclerosis
NEXT Experimental study on expression of TGF-β1 in fibrotic myocardium of rat by magnatic resonance targeted imaging
  


LINK


Tel & Fax: +8610-67113815    E-mail: editor@cjmri.cn