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Recent evidence suggests that cardiovascular (CV)\/cerebrovascular risk factors, including hyperhomocysteinemia (Hhcy), exacerbate AD pathology and risk. Yet, the underlying molecular mechanisms for this interaction remain unclear. Our lab has demonstrated that amyloid beta 40 (A\u03b240) species, and particularly A\u03b240\u2010E22Q (A\u03b2Q22; vasculotropic Dutch mutant), promote death receptor 4 and 5 (DR4\/DR5)\u2010mediated apoptosis in human cECs, barrier permeability, and angiogenic impairment. Previous studies show that Hhcy also induces EC dysfunction, but it remains unknown whether A\u03b2 and homocysteine function through common molecular mechanisms. We tested the hypotheses that Hhcy exacerbates A\u03b2\u2010induced cEC DR4\/5\u2010mediated apoptosis, barrier dysfunction, and angiogenesis defects. This study was the first to demonstrate that Hhcy specifically potentiates A\u03b2Q22\u2010mediated activation of the DR4\/5\u2010mediated extrinsic apoptotic pathway in cECs, including DR4\/5 expression, caspase 8\/9\/3 activation, cytochrome\u2010c release and DNA fragmentation. Additionally, we revealed that Hhcy intensifies the deregulation of the same cEC junction proteins mediated by A\u03b2, precipitating BBB permeability. Furthermore, Hhcy and A\u03b2Q22, impairing VEGF\u2010A\/VEGFR2 signaling and VEGFR2 endosomal trafficking, additively decrease cEC angiogenic capabilities. Overall, these results show that the presence of the CV risk factor Hhcy exacerbates A\u03b2\u2010induced cEC apoptosis, barrier dysfunction, and angiogenic impairment. This study reveals specific mechanisms through which amyloidosis and Hhcy jointly operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD\/CAA and Hhcy conditions.<\/jats:p>","DOI":"10.1111\/acel.14106","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T12:21:40Z","timestamp":1707999700000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Homocysteine potentiates amyloid \u03b2\u2010induced death receptor 4\u2010 and 5\u2010mediated cerebral endothelial cell apoptosis, blood brain barrier dysfunction and angiogenic impairment"],"prefix":"10.1111","volume":"23","author":[{"given":"Ashley","family":"Carey","sequence":"first","affiliation":[{"name":"Department of Neural Sciences, Alzheimer's Center at Temple Temple University Lewis Katz School of Medicine  Philadelphia Pennsylvania 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