Glymphatic influx and clearance are perturbed in Huntington’s disease
Hongshuai Liu, Lin Chen, Chuangchuang Zhang, Chang Liu, Yuguo Li, Liam Cheng, Yuxiao Ouyang, Catherine Rutledge, John Anderson, Zhiliang Wei, Ziqin Zhang, Hanzhang Lu, Peter C.M. van Zijl, Jeffrey J. Iliff, Jiadi Xu, Wenzhen Duan
Hongshuai Liu, Lin Chen, Chuangchuang Zhang, Chang Liu, Yuguo Li, Liam Cheng, Yuxiao Ouyang, Catherine Rutledge, John Anderson, Zhiliang Wei, Ziqin Zhang, Hanzhang Lu, Peter C.M. van Zijl, Jeffrey J. Iliff, Jiadi Xu, Wenzhen Duan
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Research Article Neuroscience

Glymphatic influx and clearance are perturbed in Huntington’s disease

Abstract

The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington’s disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure d-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice before phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further verified with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.

Authors

Hongshuai Liu, Lin Chen, Chuangchuang Zhang, Chang Liu, Yuguo Li, Liam Cheng, Yuxiao Ouyang, Catherine Rutledge, John Anderson, Zhiliang Wei, Ziqin Zhang, Hanzhang Lu, Peter C.M. van Zijl, Jeffrey J. Iliff, Jiadi Xu, Wenzhen Duan

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Figure 3

Perturbed glymphatic function and exacerbated AQP4 perivascular localization (polarization) in the manifest zQ175 HD mouse brain.

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Perturbed glymphatic function and exacerbated AQP4 perivascular localiza...
(A) Representative images of DGE signals (lower panel) in a WT mouse and a zQ175 mouse at 10 months of age. (B) Average dynamic d-glucose signals during the entire scan period from male WT and zQ75 mice. n = 5 mice/genotype. (C) Comparison of fitted clearance parameter μout d-glucose clearance rate in CSF of the third ventricle. **P < 0.01 vs. WT by standard Student’s t test. (D) Comparison of fitted clearance parameter μin d-glucose uptake rate in CSF of the third ventricle. (E) Representative images of coimmunofluorescence staining of AQP4 and collagen IV in the striatum (upper panel) and cortex (bottom panel) of 10-month-old male zQ175 and WT controls. Scale bar = 100 μm. (F) Quantification of colocalized pixels of AQP4 (green in E) and collagen IV (red in E) in the striatum of 10-month-old male zQ175 mice and WT controls. *P < 0.05 vs. WT by standard Student’s t test. (G) Quantification of colocalized pixels of AQP4 (green in E) and collagen IV (red in E) in the cortex of 10-month-old male zQ175 mice and WT controls. **P < 0.01 vs. WT by standard Student’s t test. (H) Representative images of BSA-647 fluorescent dye distribution in the brain parenchyma at 60 minutes after intra-CM injection in 10-month-old mice. Scale bar = 1 cm. The left panel shows the BSA-647 fluorescence images, and the right panel shows BSA-647 fluorescence images merged with DAPI staining images. (I) Quantification of the fluorescent dye distribution at 60 minutes after CSF tracer injection. *P < 0.05 vs. WT by standard Student’s t test.