Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease

• Published in: Neural regeneration research Vol. 13; no. 4; pp. 709 - 716
• Main Authors: Wen, Ya-Ru, Yang, Jun-Hua, Wang, Xiao, Yao, Zhi-Bin
• Format: Journal Article
• Language: English
• Published: India Wolters Kluwer India Pvt. Ltd 01.04.2018; Medknow Publications and Media Pvt. Ltd; Medknow Publications & Media Pvt. Ltd; Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China; Medknow Publications & Media Pvt Ltd; Wolters Kluwer Medknow Publications
• Subjects: Alzheimer's disease; Amyloid beta-protein; Angiogenesis; Brain research; Care and treatment; Development and progression; Dura mater; Health aspects; Immunization; Laboratory animals; Lymphatic system; Lymphatic vessels; Neovascularization; nerve regeneration; dura mater; lymphangiogenesis; amyloid-β; Alzheimer′s disease; recombinant human vascular endothelial growth factor-C; lymphatic endothelial cells; lymphatic clearance; neural regeneration; Physiological aspects; R&D; Research & development; Vascular endothelial growth factor; United States > US; China; Germany; neural regeneration; lymphatic clearance; amyloid-β; lymphangiogenesis; lymphatic endothelial cells; nerve regeneration; recombinant human vascular endothelial growth factor-C; Alzheimer's disease; dura mater
• ISSN: 1673-5374; 1876-7958
• DOI: 10.4103/1673-5374.230299

Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer's disease. The therapeutic effect of current pharmacotherapies is unsatisfactory, and some treatments cause severe side effects. The meningeal lymphatic vessels might be a new route for amyloid-β clearance. This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain. First, human lymphatic endothelial cells were treated with 100 ng/mL recombinant human vascular endothelial growth factor-C (rhVEGF-C) protein. Light microscopy verified that rhVEGF-C, a specific ligand for vascular endothelial growth factor receptor-3 (VEGFR-3), significantly promoted tube formation of human lymphatic endothelial cells in vitro. In an in vivo study, 200 μg/mL rhVEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice, once every 2 days, four times in total. Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer's disease mice. One week after rhVEGF-C administration, enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain. The Morris water maze test demonstrated that spatial cognition was restored. These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice, suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer's disease.