摘要：SummaryAmyloid β-protein (Aβ) may contribute to worsening of Alzheimer’s disease (AD) through vascular dysfunction, but the molecular mechanism involved is unknown. Usingex vivoblood vessels and primary endothelial cells from human brain microvessels, we show that patient-derived Aβ assemblies, termed amylospheroids (ASPD), exist on the microvascular surface in patients’ brains and inhibit vasorelaxation through binding to the α3 subunit of sodium, potassium-ATPase (NAKα3) in caveolae on endothelial cells. Interestingly, NAKα3 is also the toxic target of ASPD in neurons. ASPD-NAKα3 interaction elicits neurodegeneration through calcium overload in neurons, while the same interaction suppresses vasorelaxation by increasing the inactive form of endothelial nitric oxide synthase (eNOS) in endothelial cells via mitochondrial ROS and protein kinase C, independently of the physiological relaxation system. Thus, ASPD may contribute to both neuronal and vascular pathologies through binding to NAKα3. Therefore, blocking the ASPD-NAKα3 interaction may be a useful target for AD therapy.Graphical abstractDisplay OmittedHighlights•Unlike insoluble Aβ, ASPD preferentially exist on the endothelium of AD microvessels•ASPD inhibit vasorelaxation via binding to ATPase α3 present on endothelial caveolae•ASPD-NAKα3 interaction reduces NO release by increasing eNOS-Thr495phosphorylation•Unlike Aβ1-42, ASPD induce eNOS inactivation via mitochondrial ROS/PKC pathwayNeuroscience; Clinical neuroscience; Cellular neuroscience; Cell biology
