Lack of Oxygen and/or Glucose Differentially Potentiates Aβ40(e22q)- and Aβ42-Induced Cerebral Endothelial Cell Death, Barrier Dysfunction and Angiogenesis Impairment.

Cerebrovascular damage/dysfunction promote cerebral hypoperfusion early within Alzheimer's 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 AβQ22 (vasculotropic Dutch mutant) and Aβ42 promote cerebral endothelial cell (cEC) apoptosis, barrier permeability, and angiogenic impairments. Prior research indicates hypoperfusion promotes analogous EC dysfunction. Aβ accumulates within a hypoperfused environment in AD, but whether Aβ exposure of cECs under hypoperfusion potentiates dysfunction through activation of shared molecular mechanisms remains unknown. We treated cECs with Aβ40-Q22/Aβ42, 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 Aβ-induced cEC death, barrier dysfunction, inflammatory activation, and angiogenesis/wound healing failure. Hypoperfusion specifically exacerbated AβQ22-mediated cEC apoptosis, TEER/ZO1 decreases, ICAM1/IL6/IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, hypoperfusion strongly potentiated Aβ42-mediated necrosis and MMP2/pClaudin-5/IFNγ/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.