Alzheimer's Aβ assembly binds sodium pump and blocks endothelial NOS activity via ROS-PKC pathway in brain vascular endothelial cells

iScience

Kaori Satomura¹  Akiyoshi Kakita¹  Tomoya Sasahara²  Mari Tada²  Minako Hoshi³ 

[1] TAO Health Life Pharma Co., Ltd., Med-Pharma Collaboration Bldg, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan;Department for Brain and Neurodegenerative Disease Research, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, CLIK 6F 6-3-7 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan;Department of Pathology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan;

关键词: Neuroscience;    Clinical neuroscience;    Cellular neuroscience;    Cell biology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Amyloid β-protein (Aβ) may contribute to worsening of Alzheimer’s disease (AD) through vascular dysfunction, but the molecular mechanism involved is unknown. Using ex vivo blood 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.

【 授权许可】

Unknown