Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Mestre, Humberto; Hablitz, Lauren M.; Xavier, Anna L.R.; Feng, Weixi; Zou, Wenyan; Pu, Tinglin; Monai, Hiromu; Murlidharan, Giridhar; Rivera, Ruth M. Castellanos; Simon, Matthew; Pike, Martin M.; Plá, Virginia; Du, Ting; Kress, Benjamin T.; Wang, Xiaowen; Plog, Benjamin A.; Thrane, Alexander S.; Lundgaard, Iben; Abe, Yoichiro; Yasui, Masato; Thomas, John H.; Xiao, Ming; Hirase, Hajime; Asokan, Aravind; Iliff, Jeffrey J.; Nedergaard, Maiken

doi:10.7554/elife.40070

Cited by 470 publications

(507 citation statements)

References 73 publications

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“…Our simulations point to two main reasons why arterial pulsations cannot drive unidirectional fluid flow in the PVS. First, direct measurement of cortical arteriole diameters in mice using two-photon imaging shows that the amplitude of the heartbeat-driven pulsations is small (1-4% peak to peak change in arterial diameter 6,50,51 ). In humans, CT angiography has shown that pulsations drive only a maximum of 4-6% 52,53 change in the volume of the MCA (2-3% change in diameter assuming a cylindrical geometry).…”

Section: Discussionmentioning

confidence: 99%

“…Based on the experimental evidence available, we speculate that two possible mechanisms that could drive CSF flow in the PVS, namely, CSF production in the choroid plexus and osmotic pressure differences across astrocytic end feet. CSF flow through the PVS and into the brain is severely affected in aquaporin-4 (AQP4) knockout mice 1,50 . The AQP4 channel is selectively permeable to water 61,62 and is present in the choroid plexus 63 and the astrocytic endfeet 1 .…”

Section: Discussionmentioning

confidence: 99%

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Arterial pulsations drive oscillatory flow of CSF but not directional pumping

Kedarasetti

Drew

Costanzo

2020

Preprint

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The brain lacks a traditional lymphatic system for metabolite clearance. The existence a "glymphatic system" where metabolites are removed from the brain's extracellular space by convective exchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF) along the paravascular spaces (PVS) around cerebral blood vessels has been controversial for nearly a decade. While recent work has shown clear evidence of directional flow of CSF in the PVS in anesthetized mice, the driving force for the observed fluid flow remains elusive. The heartbeatdriven peristaltic pulsation of arteries has been proposed as a probable driver of directed CSF flow. In this study, we use rigorous fluid dynamic simulations to provide a physical interpretation for peristaltic pumping of fluids. Our simulations match the experimental results and show that arterial pulsations only drive oscillatory motion of CSF in the PVS. The observed directional CSF flow can be explained by naturally occurring and/or experimenter-generated pressure differences.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Arterial pulsations drive oscillatory flow of CSF but not directional pumping

Kedarasetti

Drew

Costanzo

2020

Preprint

View full text Add to dashboard Cite

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“…The role of Aqp4 in glymphatic function is, however, still a matter of discussion. The development of a functional glymphatic system in mice was shown to be correlated with the expression of Aqp4 at the astrocyte endfoot-vascular interface [62], and using several lines of Aqp4deficient mice, glymphatic tracer transport was shown to depend on intact Aqp4 function [63]. It has, however, also been argued that Aqp4 may not be solely responsible for fluid transport, but that diffusion is in fact an important regulator of paravascular flow.…”

Section: Paravascular Flowmentioning

confidence: 99%

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

2019

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Neurodegenerative and cerebrovascular diseases cause considerable human suffering, and therapy options for these two disease categories are limited or non-existing. It is an emerging notion that neurodegenerative and cerebrovascular diseases are linked in several ways, and in this review, we discuss the current status regarding vascular dysregulation in neurodegenerative disease, and conversely, how cerebrovascular diseases are associated with central nervous system (CNS) degeneration and dysfunction. The emerging links between neurodegenerative and cerebrovascular diseases are reviewed with a particular focus on pericytes-important cells that ensheath the endothelium in the microvasculature and which are pivotal for blood-brain barrier function and cerebral blood flow. Finally, we address how novel molecular and cellular insights into pericytes and other vascular cell types may open new avenues for diagnosis and therapy development for these important diseases.

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“…Impairment of meningeal lymphatics induced amyloid accumulation, and AAV1-CMV-mVEGF-C treatment enhanced CSF drainage and meningeal lymphatics function and improved spatial learning and memory. 2 As water channel aquaporin-4 (AQP4) in astrocytic end feet plays a role in glymphatic flow and maintained CSF influx in Aqp4 knockout mice 15 . In AD, AQP4 were expressed abnormally and mislocalized.…”

Section: Discussionmentioning

confidence: 99%

Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer’s disease model

Choi

Park

Kwon

et al. 2020

Preprint

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contributed equally to this investigation. Abstract Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis. Age-related changes of glymphatic-lymphatic clearance lead to the accumulation beta-amyloid (Aβ) in dementia models. In this study, focused ultrasound treatment in combination with microbubbles (FUS-MB) improved Aβ drainage in early dementia model mice, 5XFAD. FUS-MB enhanced solute Aβ clearance from brain, but not plaques, to cerebrospinal fluid (CSF) space and then deep cervical lymph node (dCLN). dCLN ligation exaggerated memory impairment and progress of plaque formation and also the beneficial effects of FUS-MB upon Aβ removal through CSF-lymphatic routes. In this ligation model, FUS-MB improved memory despite accumulation of Aβ in CSF. In conclusion, FUS-MB enhances glymphatic-lymphatic clearance of Aβ mainly by increasing brain-to-CSF Aβ drainage. We suggest that FUS-MB can delay dementia progress in early period and benefits of FUS-MB depend on the effect of Aβ disposal through CSF-lymphatics.

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Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Cited by 470 publications

References 73 publications

Arterial pulsations drive oscillatory flow of CSF but not directional pumping

Arterial pulsations drive oscillatory flow of CSF but not directional pumping

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer’s disease model

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