Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation
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Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation. / Gomolka, Ryszard Stefan; Hablitz, Lauren M; Mestre, Humberto; Giannetto, Michael; Du, Ting; Hauglund, Natalie Linea; Xie, Lulu; Peng, Weiguo; Martinez, Paula Melero; Nedergaard, Maiken; Mori, Yuki.
In: eLife, Vol. 12, e82232, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation
AU - Gomolka, Ryszard Stefan
AU - Hablitz, Lauren M
AU - Mestre, Humberto
AU - Giannetto, Michael
AU - Du, Ting
AU - Hauglund, Natalie Linea
AU - Xie, Lulu
AU - Peng, Weiguo
AU - Martinez, Paula Melero
AU - Nedergaard, Maiken
AU - Mori, Yuki
PY - 2023
Y1 - 2023
N2 - The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular endfeet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport. Yet, no studies have systematically examined how these abnormalities in structure and water transport correlate with glymphatic function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) along with intravoxel-incoherent motion (IVIM) DWI, while evaluating glymphatic function using a standard dynamic contrast-enhanced MR imaging to better understand how water transport and glymphatic function is disrupted after genetic deletion of AQP4. AQP4 KO mice had larger interstitial spaces and total brain volumes resulting in higher water content and reduced CSF space volumes, despite similar CSF production rates and vascular density compared to wildtype mice. The larger interstitial fluid volume likely resulted in increased slow but not fast MR diffusion measures and coincided with reduced glymphatic influx. This markedly altered brain fluid transport in AQP4 KO mice may result from a reduction in glymphatic clearance, leading to enlargement and stagnation of fluid in the interstitial space. Overall, diffusion MR is a useful tool to evaluate glymphatic function and may serve as valuable translational biomarker to study glymphatics in human disease.
AB - The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular endfeet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport. Yet, no studies have systematically examined how these abnormalities in structure and water transport correlate with glymphatic function. Here, we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) along with intravoxel-incoherent motion (IVIM) DWI, while evaluating glymphatic function using a standard dynamic contrast-enhanced MR imaging to better understand how water transport and glymphatic function is disrupted after genetic deletion of AQP4. AQP4 KO mice had larger interstitial spaces and total brain volumes resulting in higher water content and reduced CSF space volumes, despite similar CSF production rates and vascular density compared to wildtype mice. The larger interstitial fluid volume likely resulted in increased slow but not fast MR diffusion measures and coincided with reduced glymphatic influx. This markedly altered brain fluid transport in AQP4 KO mice may result from a reduction in glymphatic clearance, leading to enlargement and stagnation of fluid in the interstitial space. Overall, diffusion MR is a useful tool to evaluate glymphatic function and may serve as valuable translational biomarker to study glymphatics in human disease.
U2 - 10.7554/eLife.82232
DO - 10.7554/eLife.82232
M3 - Journal article
C2 - 36757363
VL - 12
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e82232
ER -
ID: 338854954