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

Tomoya Sasahara; Kaori Satomura; Mari Tada; Akiyoshi Kakita; Minako Hoshi

doi:10.1016/j.isci.2021.102936

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

iScience. 2021 Aug 4;24(9):102936. doi: 10.1016/j.isci.2021.102936. eCollection 2021 Sep 24.

Authors

Tomoya Sasahara^{1

2}, Kaori Satomura^{1

2}, Mari Tada³, Akiyoshi Kakita³, Minako Hoshi^{1

4}

Affiliations

¹ 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.
² TAO Health Life Pharma Co., Ltd., Med-Pharma Collaboration Bldg, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
³ Department of Pathology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
⁴ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan.

Abstract

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.

Keywords: Cell biology; Cellular neuroscience; Clinical neuroscience; Neuroscience.