{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:51:11Z","timestamp":1783529471767,"version":"3.55.0"},"reference-count":87,"publisher":"SAGE Publications","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2021,1,5]]},"abstract":"<jats:p>Background: Diabetes is one of the strongest disease-related risk factors for Alzheimer\u2019s disease (AD). In diabetics, hyperglycemia-induced microvascular complications are the major cause of end-organ injury, contributing to morbidity and mortality. Microvascular pathology is also an important and early feature of AD. The cerebral microvasculature may be a point of convergence of both diseases. Several lines of evidence also implicate thrombin in AD as well as in diabetes. Objective: Our objective was to investigate the role of thrombin in glucose-induced brain microvascular endothelial injury. Methods: Cultured Human brain microvascular endothelial cells (HBMVECs) were treated with 30\u200amM glucose\u00b1100\u200anM thrombin and\u00b1250\u200anM Dabigatran or inhibitors of PAR1, p38MAPK, MMP2, or MMP9. Cytotoxicity and thrombin activity assays on supernatants and western blotting for protein expression in lysates were performed. Results: reatment of HBMVECs with 30\u200amM glucose increased thrombin activity and expression of inflammatory proteins TNF\u03b1, IL-6, and MMPs 2 and 9; this elevation was reduced by the thrombin inhibitor dabigatran. Direct treatment of brain endothelial cells with thrombin upregulated p38MAPK and CREB, and induced TNF\u03b1, IL6, MMP2, and MMP9 as well as oxidative stress proteins NOX4 and iNOS. Inhibition of thrombin, thrombin receptor PAR1 or p38MAPK decrease expression of inflammatory and oxidative stress proteins, implying that thrombin may play a central role in glucose-induced endothelial injury. Conclusion: Since preventing brain endothelial injury would preserve blood-brain barrier integrity, prevent neuroinflammation, and retain intact functioning of the neurovascular unit, inhibiting thrombin, or its downstream signaling effectors, could be a therapeutic strategy for mitigating diabetes-induced dementia.<\/jats:p>","DOI":"10.3233\/jad-200658","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T20:17:46Z","timestamp":1606249066000},"page":"211-224","source":"Crossref","is-referenced-by-count":23,"title":["Thrombin Signaling Contributes to High Glucose-Induced Injury of Human Brain Microvascular Endothelial Cells"],"prefix":"10.1177","volume":"79","author":[{"given":"Haripriya","family":"Vittal Rao","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA"},{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed Waseem","family":"Bihaqi","sequence":"additional","affiliation":[{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA"},{"name":"Department of Neuroscience & Regenerative Medicine, Augusta University, Augusta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn","family":"Iannucci","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA"},{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhik","family":"Sen","sequence":"additional","affiliation":[{"name":"George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA"},{"name":"Rajendra Memorial Research 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