{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:35:16Z","timestamp":1792182916120,"version":"4.4.0"},"reference-count":63,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000304","name":"Parkinson\u2019s UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000304","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ARUK-RF2019A-003"],"award-info":[{"award-number":["ARUK-RF2019A-003"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Propagation and aggregation of prion proteins, such as tau and \u03b1-synuclein (\u03b1-syn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, might play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarization to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinson\u2019s disease, but the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences \u03b1-syn propagation dynamics, in addition to the role of propagating \u03b1-syn itself on glymphatic function.<\/jats:p>\n                  <jats:p>In this study, we used a mouse model of \u03b1-syn propagation to elucidate the impact of \u03b1-syn aggregation on glymphatic function by measuring CSF\u2013interstitial fluid exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions.<\/jats:p>\n                  <jats:p>Our results show that direct injection of \u03b1-syn preformed fibrils leads to local reduced expression of the AQP4 endfoot complex, but propagation of \u03b1-syn pathology induces an enhancement of glymphatic function, suggesting compensatory upregulation in response to increasing \u03b1-syn aggregate load.<\/jats:p>\n                  <jats:p>To determine the influence of glymphatic dysfunction on \u03b1-syn propagation dynamics, we then took a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain-to-CSF clearance of misfolded \u03b1-syn, and chronic treatment exacerbated \u03b1-syn pathology, cerebral atrophy and motor behavioural deficits in mice.<\/jats:p>\n                  <jats:p>Together, our findings show that \u03b1-syn clearance and propagation are modulated by glymphatic function. Moreover, they suggest that AQP4 complex dysregulation might contribute to glymphatic impairment associated with Parkinson\u2019s disease, supporting further mechanistic investigation of this protein complex in the disease.<\/jats:p>","DOI":"10.1093\/brain\/awaf255","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T07:38:51Z","timestamp":1751960331000},"source":"Crossref","is-referenced-by-count":24,"title":["The influence of the glymphatic system on \u03b1-synuclein propagation: the role of aquaporin-4"],"prefix":"10.1093","author":[{"given":"Douglas M","family":"Lopes","sequence":"first","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie K","family":"Llewellyn","sequence":"additional","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila E","family":"Bury","sequence":"additional","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiazheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack A","family":"Wells","sequence":"additional","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-0723","authenticated-orcid":false,"given":"Matthew E","family":"Gegg","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmo","family":"Verona","sequence":"additional","affiliation":[{"name":"Centre for Amyloidosis and Acute Phase Proteins, Department of Inflammation, Division of Medicine, University College London , London NW3 2PF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark F","family":"Lythgoe","sequence":"additional","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1250-4911","authenticated-orcid":false,"given":"Ian F","family":"Harrison","sequence":"additional","affiliation":[{"name":"Centre for Advanced Biomedical Imaging, Department of Imaging, Division of Medicine, University College London , London WC1E 6DD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"2025111811014523200_awaf255-B1","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41583-022-00603-7","article-title":"Conformational strains of pathogenic amyloid proteins in neurodegenerative diseases","volume":"23","author":"Li","year":"2022","journal-title":"Nat Rev Neurosci"},{"key":"2025111811014523200_awaf255-B2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40035-022-00293-2","article-title":"Propagation of tau and \u03b1-synuclein in 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