Aβ42 treatment of the brain side reduced the level of flotillin from endothelial cells on the blood side via FGF-2 signaling in a blood–brain barrier model

Molecular Brain

Research

Yuxin Chen¹  Yang Sun¹  Makoto Michikawa¹  Sadequl Islam¹  Kun Zou¹  Yuan Gao¹  Tomohisa Nakamura²  Tamihide Matsunaga³  Tadahiro Hashita³  Hiroyuki Sato³  Yasuyuki Shibuya⁴ 

[1] Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, 467-8601, Nagoya, Japan;Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, 467-8601, Nagoya, Japan;Department of Maxillofacial Surgery, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, 467-8601, Nagoya, Japan;Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-Dori, Mizuho-Ku, 467-8603, Nagoya, Japan;Department of Maxillofacial Surgery, Graduate School of Medical Sciences, Nagoya City University, Kawasumi 1, Mizuho-Cyo, Mizuho-Ku, 467-8601, Nagoya, Japan;

关键词: Amyloid β-protein;    Alzheimer’s disease;    Blood flotillin;    Microvascular endothelial cells;   

DOI  :  10.1186/s13041-023-01005-1

 received in 2022-09-22, accepted in 2023-01-13,  发布年份 2023

来源: Springer

【 摘 要 】

Our previous study showed that the flotillin level is decreased in the blood of patients with Alzheimer’s disease (AD) when compared to that of patients with non-AD and vascular dementia; however, the molecular mechanism remains to be determined. In this study, to elucidate whether Aβ accumulation in the brain has an effect on the blood flotillin level, we used our previously established blood–brain barrier (BBB) culture model using microvascular endothelial cells obtained from human induced pluripotent stem cells (iBMECs) and astrocytes prepared from rat cortex. In this BBB model with iBMECs plated on the upper compartment (blood side) and astrocytes plated on the lower compartment (brain side), the trans-endothelial electrical resistance values are high (over 1500 Ωm2) and stable during experiments. We found that the addition of Aβ42 (0.5 and 2 µM) to the brain side significantly reduced the level of flotillin secreted by iBMECs on the blood side. The level of basic fibroblast growth factor (FGF-2) in the brain side was significantly reduced by Aβ42 treatment, and was accompanied by a reduction in the level of phosphorylation of the fibroblast growth factor receptor in iBMECs. The brain-side Aβ42 treatment-induced reduction of flotillin secretion into the blood side was restored in a dose-dependent manner by the addition of FGF-2 into the brain side. These results indicated that Aβ accumulation in the brain side reduced FGF-2 release from astrocytes, which attenuated FGF-2-mediated iBMECs signaling via the FGF-2 receptor, and thereby reduced flotillin secretion from iBMECs on the blood side. Our findings revealed a novel signaling pathway crossing the BBB from the brain side to the blood side, which is different from the classical intramural periarterial drainage or lymphatic-system-to-blood pathway.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

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