Alzheimer’s Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway

Abstract

AbstractAmyloid β-protein (Aβ) may contribute to worsening of Alzheimer’s disease (AD) through vascular dysfunction, but the actual molecular mechanisms remain controversial. Using ex-vivo blood vessels and primary endothelial cells derived from human brain microvessels, we revealed that patient-derived Aβ assemblies, termed amylospheroids (ASPD), exist on the microvascular surface in patient brains and inhibit vasorelaxation through binding to the α3 subunit of sodium, potassium-ATPase (NAKα3) on endothelial cells. Interestingly, NAKα3 also serves as the toxic target of ASPD in neurons. ASPD elicit neurodegeneration through calcium overload, while ASPD suppress vasorelaxation by inhibiting nitric oxide (NO) production. ASPD-NAKα3 interaction on cerebrovascular endothelial cells disturbs the NO release by inactivating endothelial NO synthase through mitochondrial reactive oxygen species and protein kinase C. The findings suggest that ASPD may dually contribute to neuronal and vascular pathologies through binding to NAKα3. Thus, blocking the ASPD-NAKα3 interaction may be a useful target for AD therapy.