{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:50:08Z","timestamp":1787010608098,"version":"build-2736575974"},"posted":{"date-parts":[[2024,11,14]]},"group-title":"Neuroscience","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T00:00:00Z","timestamp":1731542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["NS104386"],"award-info":[{"award-number":["NS104386"]}]},{"name":"NIH","award":["AG078245"],"award-info":[{"award-number":["AG078245"]}]},{"name":"NIH","award":["HL168009"],"award-info":[{"award-number":["HL168009"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cerebral Amyloid Angiopathy (CAA), characterized by amyloid-\u03b2 (A\u03b2) accumulation within perivascular spaces (PVS), contributes to vascular damage and inflammation in Alzheimer\u2019s disease (AD). Despite its significance, the mechanisms driving A\u03b2 deposition in PVS and the resulting vascular pathology remain poorly understood. Growing evidence suggests that fibrinogen, the main component in blood clots, interacts with A\u03b2 and exacerbates inflammation in AD. Fibrinogen also co-deposits with A\u03b2 in the PVS of CAA-positive vessels in the brains of hereditary CAA patients. However, the mechanisms by which fibrinogen contributes to cerebrovascular impairment remain poorly understood. To investigate this, we used TgSwDI transgenic mice, which develop robust CAA pathology, and observed a significant increase in fibrin(ogen) extravasation and colocalization with A\u03b2 in the PVS. Moreover, we observed a significant aquaporin-4 (AQP4) depolarization in CAA-laden blood vessels of TgSwDI mice, which correlated with fibrin(ogen)-A\u03b2 colocalization. Given AQP4 crucial role in A\u03b2 clearance through glymphatic pathway, its depolarization may disrupt critical A\u03b2 clearance, thereby exacerbating CAA pathology. Additionally, Caveolin-1, a protein involved in non-specific transcytosis across the endothelium, significantly increased with age in TgSwDI mice and correlated with fibrin(ogen) extravasation. To further explore the relationship between fibrin(ogen) and these cerebrovascular alterations, we depleted fibrinogen in TgSwDI mice using siRNA approach. This intervention resulted in decreased CAA, restored polarized expression of AQP4, reduced caveolin-1 levels, attenuated microglial activation, and improved spatial memory in fibrinogen-depleted TgSwDI mice. These findings suggest that targeting fibrinogen could be a promising strategy for mitigating CAA pathology and its associated cerebrovascular pathology.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Our study uncovers the mechanism by which fibrin(ogen)-A\u03b2 colocalization exacerbates CAA pathology. Our findings highlight the potential link between fibrinogen\/ fibrin(ogen)-A\u03b2 colocalization and AQP4 depolarization thereby exacerbating CAA pathology. The age-dependent increase of endothelial caveolin-1 could facilitate fibrin(ogen) extravasation, assisting the later to binds to A\u03b2 in the perivascular space which ultimately induce microglial neuroinflammation and AQP4 depolarization, thus exacerbating CAA pathology. Furthermore, fibrinogen depletion could mitigate CAA severity, reduce microglial activation, restore AQP4 polarization and memory impairment. These results suggest that targeting fibrinogen and caveolin-1-mediated transcytosis may offer new strategies to address CAA-associated cerebrovascular pathology.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.11.11.623066","type":"posted-content","created":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T12:00:12Z","timestamp":1731585612000},"source":"Crossref","is-referenced-by-count":2,"title":["Aquaporin-4 and Caveolin-1 as Mediators of Fibrinogen-Driven Cerebrovascular Pathology in Cerebral Amyloid Angiopathy"],"prefix":"10.64898","author":[{"given":"Vishal","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Rochakim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ferraresso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khushi","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnab","family":"Choudhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian J.","family":"Kastrup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0715-7222","authenticated-orcid":false,"given":"Hyung Jin","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072722000497000_2024.11.11.623066v4.1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-015-0261-z"},{"key":"2025072722000497000_2024.11.11.623066v4.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00330-015-3834-9"},{"key":"2025072722000497000_2024.11.11.623066v4.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0522-3"},{"key":"2025072722000497000_2024.11.11.623066v4.4","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2343040197"},{"key":"2025072722000497000_2024.11.11.623066v4.5","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000016"},{"key":"2025072722000497000_2024.11.11.623066v4.6","doi-asserted-by":"publisher","DOI":"10.5853\/jos.2015.17.1.17"},{"key":"2025072722000497000_2024.11.11.623066v4.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2008.01.017"},{"key":"2025072722000497000_2024.11.11.623066v4.8","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000327887.64299.a4"},{"key":"2025072722000497000_2024.11.11.623066v4.9","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410300503"},{"key":"2025072722000497000_2024.11.11.623066v4.10","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003184"},{"key":"2025072722000497000_2024.11.11.623066v4.11","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22516"},{"key":"2025072722000497000_2024.11.11.623066v4.12","doi-asserted-by":"publisher","DOI":"10.1007\/s00234-021-02718-7"},{"key":"2025072722000497000_2024.11.11.623066v4.13","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1812-4"},{"key":"2025072722000497000_2024.11.11.623066v4.14","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30318-1"},{"key":"2025072722000497000_2024.11.11.623066v4.15","doi-asserted-by":"crossref","unstructured":"S. Peng , J. Liu , C. Liang , L. Yang , G. Wang , Aquaporin-4 in glymphatic system, and its implication for central nervous system disorders. Neurobiol Dis 179, 106035 (2023).","DOI":"10.1016\/j.nbd.2023.106035"},{"key":"2025072722000497000_2024.11.11.623066v4.16","doi-asserted-by":"crossref","unstructured":"R. Owasil et al., The Pattern of AQP4 Expression in the Ageing Human Brain and in Cerebral Amyloid Angiopathy. Int J Mol Sci 21 (2020).","DOI":"10.3390\/ijms21041225"},{"key":"2025072722000497000_2024.11.11.623066v4.17","doi-asserted-by":"crossref","first-page":"e70164","DOI":"10.1002\/alz.70164","article-title":"Aquaporin 4 modulation drives amyloid burden and cognitive abilities in an APPPS1 mouse model of Alzheimer\u2019s disease","volume":"21","year":"2025","journal-title":"Alzheimers Dement"},{"key":"2025072722000497000_2024.11.11.623066v4.18","doi-asserted-by":"crossref","unstructured":"P. Marazuela et al., Circulating AQP4 Levels in Patients with Cerebral Amyloid Angiopathy-Associated Intracerebral Hemorrhage. J Clin Med 10 (2021).","DOI":"10.3390\/jcm10050989"},{"key":"2025072722000497000_2024.11.11.623066v4.19","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-015-9446-1"},{"key":"2025072722000497000_2024.11.11.623066v4.20","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3233\/JAD-150949","article-title":"Aquaporin-4 and Alzheimer\u2019s Disease","volume":"52","year":"2016","journal-title":"J Alzheimers Dis"},{"key":"2025072722000497000_2024.11.11.623066v4.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.01.023"},{"key":"2025072722000497000_2024.11.11.623066v4.22","doi-asserted-by":"crossref","unstructured":"M. Simon et al., Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid beta plaque formation in mice. Alzheimers Res Ther 14, 59 (2022).","DOI":"10.1186\/s13195-022-00999-5"},{"key":"2025072722000497000_2024.11.11.623066v4.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.05.014"},{"key":"2025072722000497000_2024.11.11.623066v4.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.03.007"},{"key":"2025072722000497000_2024.11.11.623066v4.25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070304"},{"key":"2025072722000497000_2024.11.11.623066v4.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.10.030"},{"key":"2025072722000497000_2024.11.11.623066v4.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1921327117"},{"key":"2025072722000497000_2024.11.11.623066v4.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2019.146547"},{"key":"2025072722000497000_2024.11.11.623066v4.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2453-z"},{"key":"2025072722000497000_2024.11.11.623066v4.30","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-008-0659-8"},{"key":"2025072722000497000_2024.11.11.623066v4.31","doi-asserted-by":"publisher","DOI":"10.1113\/JP272558"},{"key":"2025072722000497000_2024.11.11.623066v4.32","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-013-9797-z"},{"key":"2025072722000497000_2024.11.11.623066v4.33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M312946200"},{"key":"2025072722000497000_2024.11.11.623066v4.34","doi-asserted-by":"publisher","DOI":"10.1369\/0022155414546692"},{"key":"2025072722000497000_2024.11.11.623066v4.35","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0925-9"},{"key":"2025072722000497000_2024.11.11.623066v4.36","doi-asserted-by":"crossref","unstructured":"S. Saito et al., Taxifolin inhibits amyloid-beta oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy. Acta Neuropathol Commun 5, 26 (2017).","DOI":"10.1186\/s40478-017-0429-5"},{"key":"2025072722000497000_2024.11.11.623066v4.37","doi-asserted-by":"publisher","DOI":"10.1007\/BF00691332"},{"key":"2025072722000497000_2024.11.11.623066v4.38","doi-asserted-by":"publisher","DOI":"10.1038\/srep06588"},{"key":"2025072722000497000_2024.11.11.623066v4.39","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X15608396"},{"key":"2025072722000497000_2024.11.11.623066v4.40","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X16629976"},{"key":"2025072722000497000_2024.11.11.623066v4.41","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.109.565119"},{"key":"2025072722000497000_2024.11.11.623066v4.42","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014559"},{"key":"2025072722000497000_2024.11.11.623066v4.43","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s44161-021-00006-4","article-title":"Aortic intimal resident macrophages are essential for maintenance of the non-thrombogenic intravascular state","volume":"1","year":"2022","journal-title":"Nat Cardiovasc Res"},{"key":"2025072722000497000_2024.11.11.623066v4.44","doi-asserted-by":"publisher","DOI":"10.1111\/jth.15877"},{"key":"2025072722000497000_2024.11.11.623066v4.45","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012537"},{"key":"2025072722000497000_2024.11.11.623066v4.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.01.043"},{"key":"2025072722000497000_2024.11.11.623066v4.47","doi-asserted-by":"crossref","unstructured":"L. S. Robison et al., Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy. J Neuroinflammation 16, 144 (2019).","DOI":"10.1186\/s12974-019-1534-0"},{"key":"2025072722000497000_2024.11.11.623066v4.48","doi-asserted-by":"crossref","unstructured":"S. E. Setti , T. Flanigan , J. Hanig , S. Sarkar , Assessment of sex-related neuropathology and cognitive deficits in the Tg-SwDI mouse model of Alzheimer\u2019s disease. Behav Brain Res 428, 113882 (2022).","DOI":"10.1016\/j.bbr.2022.113882"},{"key":"2025072722000497000_2024.11.11.623066v4.49","doi-asserted-by":"publisher","DOI":"10.1385\/JMN:21:1:65"},{"key":"2025072722000497000_2024.11.11.623066v4.50","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2230"},{"key":"2025072722000497000_2024.11.11.623066v4.51","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62993-8"},{"key":"2025072722000497000_2024.11.11.623066v4.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.03.043"},{"key":"2025072722000497000_2024.11.11.623066v4.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.02.043"},{"key":"2025072722000497000_2024.11.11.623066v4.54","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2003.07.004"},{"key":"2025072722000497000_2024.11.11.623066v4.55","doi-asserted-by":"crossref","unstructured":"T. Y. Ha et al., Age-related increase in caveolin-1 expression facilitates cell-to-cell transmission of alpha-synuclein in neurons. Mol Brain 14, 122 (2021).","DOI":"10.1186\/s13041-021-00834-2"},{"key":"2025072722000497000_2024.11.11.623066v4.56","doi-asserted-by":"publisher","DOI":"10.1038\/emm.2006.16"},{"key":"2025072722000497000_2024.11.11.623066v4.57","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3020-14.2014"},{"key":"2025072722000497000_2024.11.11.623066v4.58","doi-asserted-by":"crossref","unstructured":"K. Ishida et al., Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med 219 (2022).","DOI":"10.1084\/jem.20211275"},{"key":"2025072722000497000_2024.11.11.623066v4.59","doi-asserted-by":"crossref","unstructured":"T. J. Pedersen , S. A. Keil , W. Han , M. X. Wang , J. J. Iliff , The effect of aquaporin-4 mis-localization on Abeta deposition in mice. Neurobiol Dis 181, 106100 (2023).","DOI":"10.1016\/j.nbd.2023.106100"},{"key":"2025072722000497000_2024.11.11.623066v4.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2019.11.008"},{"key":"2025072722000497000_2024.11.11.623066v4.61","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.2c00033"},{"key":"2025072722000497000_2024.11.11.623066v4.62","first-page":"655","article-title":"Microtechnical Demonstration of Iron: A Criticism of its Methods","volume":"12","year":"1936","journal-title":"Am J Pathol"},{"key":"2025072722000497000_2024.11.11.623066v4.63","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-05-01619.2001"},{"key":"2025072722000497000_2024.11.11.623066v4.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2010.12.013"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.11.11.623066","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:04:16Z","timestamp":1782277456000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.11.11.623066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,14]]},"references-count":64,"URL":"https:\/\/doi.org\/10.1101\/2024.11.11.623066","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1002\/alz.71030","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,11,14]]},"subtype":"preprint"}}