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Impaired glymphatic function and clearance of tau in an Alzheimer's disease model

Harrison, IF; Ismail, O; Machhada, A; Colgan, N; Ohene, Y; Nahavandi, P; Ahmed, Z; ... Lythgoe, MF; + view all (2020) Impaired glymphatic function and clearance of tau in an Alzheimer's disease model. Brain , 143 pp. 2576-2593. 10.1093/brain/awaa179. Green open access

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Abstract

The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-b and tau, which accumulate in the brain in Alzheimer’s disease. Further, tau protein transference via the extracellular space, the compartment that is cleared by the glymphatic pathway, allows for its neuronto- neuron propagation, and the regional progression of tauopathy in the disorder. The glymphatic system therefore represents an exciting new target for Alzheimer’s disease. Here we aim to understand the involvement of glymphatic CSF-ISF exchange in tau pathology. First, we demonstrate impaired CSF-ISF exchange and AQP4 polarization in a mouse model of tauopathy, suggesting that this clearance pathway may have the potential to exacerbate or even induce pathogenic accumulation of tau. Subsequently, we establish the central role of AQP4 in the glymphatic clearance of tau from the brain; showing marked impaired glymphatic CSFISF exchange and tau protein clearance using the novel AQP4 inhibitor, TGN-020. As such, we show that this system presents as a novel druggable target for the treatment of Alzheimer’s disease, and possibly other neurodegenerative diseases alike.

Type: Article
Title: Impaired glymphatic function and clearance of tau in an Alzheimer's disease model
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awaa179
Publisher version: https://doi.org/http://doi.org/10.1093/brain/awaa1...
Language: English
Additional information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Keywords: Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, glymphatic, tau, aquaporin-4, Alzheimer's disease, rTg4510, MOUSE MODEL, PERIVASCULAR DRAINAGE, EXTRACELLULAR-SPACE, TRANSGENIC MICE, BRAIN, PATHOLOGY, AQUAPORIN-4, PROPAGATION, TRANSPORT, TANGLE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Imaging
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10114764
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