Fig. 2

Specific mechanisms by which chronic exercise improves Aβ metabolism. Wnt/FZ forms a ternary cell surface complex with the co-receptor low-density lipoprotein receptor related protein 5/6 (LRP5/6), leading to the recruitment of scatterin and Axin to FZ, which in turn causes activation of the upstream of the Wnt/β-catenin signaling pathway in BBB endothelial cells, and subsequently, this interaction results in a lower phosphorylation of β-catenin in the cytoplasm and stabilization of β-catenin.  β-Catenin enters the nucleus and binds to the lymphatic enhancer factor (Lef)/T-cell factor (TCF) transcriptional factors, leading to the upregulation of claudin-3, GLUT-1, platelet derived growth factor B (PDGF-B) and P-glycoprotein (P-gp), where P-gp transports Aβ from BBB endothelial cells to blood. When Wnt/β-catenin signaling is inhibited in BBB endothelial cells, intracytoplasmic β-catenin is interconnected with the destruction complex, which is mainly composed of colonic adenoma virus (APC), Axin and GSK3β. Disruption of the complex can lead to phosphorylation of β-catenin, followed by separation of the phosphorylated β-catenin from the complex, ubiquitination and degradation of the proteasome, causing a decrease in the level and transcriptional activity of β-catenin in the nucleus, and ultimately dysfunction of the BBB [98]