Molecular Brain (Jan 2023)

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

  • Tomohisa Nakamura,
  • Tadahiro Hashita,
  • Yuxin Chen,
  • Yuan Gao,
  • Yang Sun,
  • Sadequl Islam,
  • Hiroyuki Sato,
  • Yasuyuki Shibuya,
  • Kun Zou,
  • Tamihide Matsunaga,
  • Makoto Michikawa

DOI
https://doi.org/10.1186/s13041-023-01005-1
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 10

Abstract

Read online

Abstract 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.

Keywords