- Alzheimer's Aฮฒ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway in brain vascular endothelial cells.
Alzheimer's Aฮฒ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway in brain vascular endothelial cells.
Amyloid ฮฒ-protein (Aฮฒ) may contribute to worsening of Alzheimer's disease (AD) through vascular dysfunction, but the molecular mechanism involved is unknown. Using exย vivo blood vessels and primary endothelial cells from human brain microvessels, we show that patient-derived Aฮฒ assemblies, termed amylospheroids (ASPD), exist on the microvascular surface in patients' brains and inhibit vasorelaxation through binding to the ฮฑ3 subunit of sodium, potassium-ATPase (NAKฮฑ3) in caveolae on endothelial cells. Interestingly, NAKฮฑ3 is also the toxic target of ASPD in neurons. ASPD-NAKฮฑ3 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 NAKฮฑ3. Therefore, blocking the ASPD-NAKฮฑ3 interaction may be a useful target for AD therapy.