Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

Qi Wang, Xiaomin Huang, Yixun Su, Guowei Yin, Shouyu Wang, Bin Yu, Hui Li, Junhua Qi, Hui Chen, Wen Zeng, Kai Zhang, Alexei Verkhratsky, Jianqin Niu, Chenju Yi

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for Alzheimer's disease pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier is increasingly recognized as a major contributor to the pathophysiology of Alzheimer's disease, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve blood-brain barrier function in the context of Alzheimer's disease. Here, we showed dysfunctional blood-brain barrier in patients with Alzheimer's disease reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells. In the APPswe/PS1dE9 (APP/PS1) mouse model of Alzheimer's disease, blood-brain barrier dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and amyloid-β-treated brain endothelial cells, we found suppressed Wnt/β-catenin signalling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signalling) to activate Wnt/β-catenin pathway, blood-brain barrier malfunction was restored by preventing amyloid-β-induced brain endothelial cells impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate blood-brain barrier malfunction induced by amyloid-β, which may be a potential treatment strategy for Alzheimer's disease.

Original languageEnglish
Pages (from-to)4474-4488
Number of pages15
JournalBrain
Volume145
Issue number12
Early online date5 Jul 2022
DOIs
Publication statusPublished - 1 Dec 2022

Keywords

  • blood-brain barrier
  • endothelial cells
  • LRP6
  • opsin-free optogenetics
  • beta Catenin
  • Blood-Brain Barrier/metabolism
  • Mice, Transgenic
  • Animals
  • Endothelial Cells/metabolism
  • Mice
  • Alzheimer Disease/metabolism
  • Amyloid beta-Peptides/metabolism
  • Wnt Signaling Pathway
  • Disease Models, Animal

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