{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T07:41:13Z","timestamp":1772350873609,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cerebrovascular damage\/dysfunction promote cerebral hypoperfusion early within Alzheimer\u2019s Disease (AD). Cerebral hypoperfusion is also a common consequence of cardiovascular risk factors\/diseases, typically manifesting in midlife when AD pathology initiates, and contributing to AD onset\/progression. We demonstrated that A\u03b2Q22 (vasculotropic Dutch mutant) and A\u03b242 promote cerebral endothelial cell (cEC) apoptosis, barrier permeability, and angiogenic impairments. Prior research indicates hypoperfusion promotes analogous EC dysfunction. A\u03b2 accumulates within a hypoperfused environment in AD, but whether A\u03b2 exposure of cECs under hypoperfusion potentiates dysfunction through activation of shared molecular mechanisms remains unknown. We treated cECs with A\u03b240-Q22\/A\u03b242, glucose deprivation (GD), or both under normoxia or hypoxia. Cell death, barrier dysfunction\/permeability, proinflammatory activation, and angiogenesis impairment were evaluated. Overall, GD and\/or hypoxia potentiated A\u03b2-induced cEC death, barrier dysfunction, inflammatory activation, and angiogenesis\/wound healing failure. Hypoperfusion specifically exacerbated A\u03b2Q22-mediated cEC apoptosis, TEER\/ZO1 decreases, ICAM1\/IL6\/IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, hypoperfusion strongly potentiated A\u03b242-mediated necrosis and MMP2\/pClaudin-5\/IFN\u03b3\/IL12p70 increases. GD exerted stronger increases in caspase-3 activation\/apoptosis and MMP2\/ICAM1 expression, while hypoxia increased necrosis and ZO1\/pro-angiogenic proteins. This study reveals specific, selective mechanisms that hypoxia\/GD and amyloidosis mutually activate to produce cEC dysfunction, highlighting new molecular targets against vascular pathology in AD\/CAA comorbid with hypoperfusion.<\/jats:p>","DOI":"10.3390\/cells15050424","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:05:16Z","timestamp":1772211916000},"page":"424","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lack of Oxygen and\/or Glucose Differentially Potentiates A\u03b240e22q- and A\u03b242-Induced Cerebral Endothelial Cell Death, Barrier Dysfunction and Angiogenesis Impairment"],"prefix":"10.3390","volume":"15","author":[{"given":"Ashley","family":"Carey","sequence":"first","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetyana","family":"Buzhdygan","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2047-222X","authenticated-orcid":false,"given":"Silvia","family":"Fossati","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(2024). 2024 Alzheimer\u2019s disease facts and figures. 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