{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:02:25Z","timestamp":1787022145399,"version":"build-2736575974"},"reference-count":108,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001459","name":"Ministry of Education - Singapore","doi-asserted-by":"publisher","award":["#MOE2017-T3-1-002"],"award-info":[{"award-number":["#MOE2017-T3-1-002"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001348","name":"Agency for Science, Technology and Research","doi-asserted-by":"publisher","award":["grant #1716424003"],"award-info":[{"award-number":["grant #1716424003"]}],"id":[{"id":"10.13039\/501100001348","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Vascular cognitive impairment (VCI) is the second leading cause of dementia with limited treatment options, characterised by cerebral hypoperfusion-induced white matter rarefaction (WMR). Subcortical VCI is the most common form of VCI, but the underlying reasons for region susceptibility remain elusive. Recent studies employing the bilateral cortical artery stenosis (BCAS) method demonstrate that various inflammasomes regulate white matter injury and blood-brain barrier dysfunction but whether caspase-1 inhibition will be beneficial remains unclear. To address this, we performed BCAS on C57\/BL6 mice to study the effects of Ac-YVAD-cmk, a caspase-1 inhibitor, on the subcortical and cortical regions. Cerebral blood flow (CBF), WMR, neuroinflammation and the expression of tight junction-related proteins associated with blood-brain barrier integrity were assessed 15 days post BCAS. We observed that Ac-YVAD-cmk restored CBF, attenuated BCAS-induced WMR and restored subcortical myelin expression. Within the subcortical region, BCAS activated the NLRP3\/caspase-1\/interleukin-1beta axis only within the subcortical region, which was attenuated by Ac-YVAD-cmk. Although we observed that BCAS induced significant increases in VCAM-1 expression in both brain regions that were attenuated with Ac-YVAD-cmk, only ZO-1 and occludin were observed to be significantly altered in the subcortical region. Here we show that caspase-1 may contribute to subcortical regional susceptibility in a mouse model of VCI. In addition, our results support further investigations into the potential of Ac-YVAD-cmk as a novel treatment strategy against subcortical VCI and other conditions exhibiting cerebral hypoperfusion-induced WMR.<\/jats:p>","DOI":"10.1371\/journal.pone.0299703","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T13:35:36Z","timestamp":1713360936000},"page":"e0299703","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hope for vascular cognitive impairment: Ac-YVAD-cmk as a novel treatment against white matter rarefaction"],"prefix":"10.1371","volume":"19","author":[{"given":"Yun-An","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li Si","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9516-5515","authenticated-orcid":true,"given":"Wei Thye","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4630-6684","authenticated-orcid":true,"given":"Wei Liang","family":"Sim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Takakuni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8608-058X","authenticated-orcid":true,"given":"Satoshi","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Ihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-0939","authenticated-orcid":true,"given":"Thiruma Valavan","family":"Arumugam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred Wai-Shiu","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6119-701X","authenticated-orcid":true,"given":"Gavin Stewart","family":"Dawe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"issue":"1","key":"pone.0299703.ref001","doi-asserted-by":"crossref","first-page":"H1","DOI":"10.1152\/ajpheart.00581.2016","article-title":"Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging","volume":"312","author":"P Toth","year":"2017","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"9","key":"pone.0299703.ref002","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1161\/STR.0b013e3182299496","article-title":"Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association\/american stroke association","volume":"42","author":"PB Gorelick","year":"2011","journal-title":"Stroke"},{"issue":"25","key":"pone.0299703.ref003","first-page":"3326","article-title":"Vascular Cognitive Impairment and Dementia: JACC Scientific Expert Panel","volume":"73","author":"C Iadecola","year":"2019","journal-title":"J Am Coll Cardiol"},{"issue":"7","key":"pone.0299703.ref004","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/S1474-4422(10)70104-6","article-title":"Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges","volume":"9","author":"L Pantoni","year":"2010","journal-title":"Lancet Neurol"},{"issue":"11","key":"pone.0299703.ref005","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.exger.2012.05.023","article-title":"Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain","volume":"47","author":"DR Thal","year":"2012","journal-title":"Exp Gerontol"},{"issue":"6005","key":"pone.0299703.ref006","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1126\/science.1199139","article-title":"Neuroscience. 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