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

Harrison, Ian F, Ismail, Ozama, Machhada, Asif, Colgan, Niall, Ohene, Yolanda, Nahavandi, Payam, Ahmed, Zeshan, Fisher, Alice, Meftah, Soraya, Murray, Tracey K, Ottersen, Ole P, Nagelhus, Erlend A, O’Neill, Michael J, Wells, Jack A, Lythgoe, Mark F·2020·Brain
DOI 10.1093/brain/awaa179PMC PMC7447521
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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-β 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 neuron-to-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 CSF-ISF 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.

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Metadata

Authors
Harrison, I. F., Ismail, O., Machhada, A., Colgan, N., Ohene, Y., Nahavandi, P., Ahmed, Z., Fisher, A., Meftah, S., Murray, T. K., Ottersen, O. P., Nagelhus, E. A., O’Neill, M. J., Wells, J. A., & Lythgoe, M. F.
Affiliations
  • UCL Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London, London, UK
  • Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, UK
  • Office of the President, Karolinska Institutet, Stockholm, Sweden
  • Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2020-07-23
Volume
143
Issue
8
Pages
2576-2593
ISSN
  • 0006-8950
  • 1460-2156
DOI
10.1093/brain/awaa179
PMC
PMC7447521
Cited by
672
References
19
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor, 1 d)
Funders
  • Eli Lilly and Company
  • Engineering and Physical Sciences Research Council
  • EPSRC (EP/N034864/1)
  • Alzheimer’s Research UK (ARUK-RF2019A-003)
  • Parkinson’s UK
  • Wellcome Trust
  • Royal Society Sir Henry Dale Fellowship (204624/Z/16/Z)
  • King’s College London
  • UCL Comprehensive Cancer Imaging Centre
  • Regenerative Medicine Platform Safety Hub (MR/K026739/1)

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