{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:00:07Z","timestamp":1785427207445,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,7]]},"group-title":"Neuroscience","reference-count":86,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01NS104127"],"award-info":[{"award-number":["R01NS104127"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG062572"],"award-info":[{"award-number":["R01AG062572"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Edward N. and Della L. Thome Memorial Foundation Awards Program in Alzheimer's Disease Drug Discovery Research"},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["AARG-20-685,663"],"award-info":[{"award-number":["AARG-20-685,663"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PA Cure"],"award-info":[{"award-number":["PA Cure"]}],"id":[{"id":"https:\/\/ror.org\/00ra1fg11","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020334","name":"Karen Toffler Charitable Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100020334","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH NHLBI T32 Training Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Disrupted brain hemodynamics and cerebrovascular damage resulting in cerebral hypoperfusion occur early within Alzheimer\u2019s Disease (AD) pathogenesis. Cerebral hypoperfusion is also an extremely common consequence of cardiovascular risk factors and diseases (CVRFs\/CVDs), which usually manifest in midlife, when AD pathology initiates, and actively contribute to AD onset and progression. Previously our lab has demonstrated that the vasculotropic Dutch mutant, A\u03b2Q22, and A\u03b242 promote endothelial cells (ECs) apoptosis, barrier permeability, and angiogenic impairments. Prior research has indicated that hypoperfusion promotes analogous EC dysfunction. A\u03b2 deposition occurs within a hypoperfused environment in AD, but whether exposure of cerebral ECs to A\u03b2 under hypoperfusion results in potentiated cerebral EC dysfunction through activation of common molecular mechanisms remained unknown.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Human cerebral ECs were treated with A\u03b240-Q22 or A\u03b242, glucose deprivation (GD), or a combination of both, under normoxia or hypoxia conditions. Cell death mechanisms (apoptosis\/necrosis), endothelial barrier dysfunction\/permeability (TEER\/barrier-regulating proteins\/proinflammatory activation), and angiogenesis impairment (vessel branching\/VEGF signaling) were evaluated.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Reduction of glucose and\/or oxygen potentiates A\u03b2-induced cerebral EC death, barrier instability, junction protein dysregulation, inflammatory activation, and angiogenesis\/wound healing failure. In particular, hypoperfusion exacerbates A\u03b2Q22-mediated cerebral EC apoptosis, TEER\/ZO1 decreases, ICAM1, IL6, and IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, when in combination with A\u03b242, hypoperfusion more strongly potentiates cerebral EC necrosis as well as increases in MMP2, phosphorylated claudin-5, IFN\u03b3, and IL12p70 expression. Additionally, this study identified that GD exerts stronger effects on promoting increases in cerebral EC caspase-3 activation, apoptosis, and MMP2\/ICAM1 expression, while hypoxia particularly increases necrosis, ZO1 expression, and pro-angiogenic protein expression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study reveals specific and selective mechanisms through which hypoxia, low glucose and amyloidosis mutually operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in AD\/CAA comorbid with hypoperfusion conditions.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Depriving cerebral endothelial cells of glucose and\/or oxygen potentiates A\u03b2-induced endothelial dysfunction, differentially promoting increased cell death, barrier instability and dysregulation of blood brain barrier proteins, inflammatory activation, and angiogenesis and wound healing failure, in relation to the specific peptide and low glucose or oxygen conditions.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Under hypoperfusion conditions, A\u03b2Q22 more strongly exacerbates increases in apoptosis, ICAM1, IL6, and IL8 expression, and monocyte migration and decreases in TEER, ZO1 expression, and wound healing, revealing that the vasculotropic A\u03b2Q22 produces even stronger vascular effects when in combination with hypoperfusion.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Under hypoperfusion conditions, A\u03b242 more strongly potentiates increases in necrosis and MMP2, phosphorylated claudin-5, IFN\u03b3, and IL12p70 expression.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Glucose deprivation exerts stronger effects on increasing caspase-3 activation, apoptosis, and MMP2 and ICAM1 expression, while hypoxia displays stronger effects on increasing necrosis and ZO1 and pro-angiogenic protein expression.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>We demonstrated that A\u03b2Q22 more intensely promotes vascular dysfunction when in combination with hypoperfusion conditions versus A\u03b242.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>verall, results from this study point to the importance of monitoring and preventing cerebral hypoperfusion particularly during midlife, when AD pathology begins to develop, to prevent this early pathology from working with A\u03b2 to create a more detrimental dementia trajectory, and highlights new targets for possible therapeutic or preventive strategies.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.05.680546","type":"posted-content","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T09:20:13Z","timestamp":1759828813000},"source":"Crossref","is-referenced-by-count":0,"title":["LACK OF OXYGEN AND\/OR GLUCOSE DIFFERENTIALLY POTENTIATES A\u03b240\n                  <sub>E22Q<\/sub>\n                  - AND A\u03b242-INDUCED CEREBRAL ENDOTHELIAL CELL DEATH, BARRIER DYSFUNCTION AND ANGIOGENESIS IMPAIRMENT"],"prefix":"10.64898","author":[{"given":"Ashley","family":"Carey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetyana","family":"Buzhdygan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Fossati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111016550399000_2025.10.05.680546v2.1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13809"},{"key":"2025111016550399000_2025.10.05.680546v2.2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"2025111016550399000_2025.10.05.680546v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.10.062"},{"key":"2025111016550399000_2025.10.05.680546v2.4","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-139584"},{"key":"2025111016550399000_2025.10.05.680546v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0281-2"},{"key":"2025111016550399000_2025.10.05.680546v2.6","doi-asserted-by":"crossref","unstructured":"Gatti, L. , et al., Understanding the Pathophysiology of Cerebral Amyloid Angiopathy. 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