title: Annexin A1 restores Aβ1-42-induced blood-brain barrier disruption through the inhibition of RhoA-ROCK signaling pathway.
abstract: The blood-brain barrier (BBB) is composed of brain capillary endothelial cells and has an important role in maintaining homeostasis of the brain separating the blood from the parenchyma of the central nervous system (CNS). It is widely known that disruption of the BBB occurs in various neurodegenerative diseases, including Alzheimer's disease (AD). Annexin A1 (ANXA1), an anti-inflammatory messenger, is expressed in brain endothelial cells and regulates the BBB integrity. However, its role and mechanism for protecting BBB in AD have not been identified. We found that β-Amyloid 1-42 (Aβ42)-induced BBB disruption was rescued by human recombinant ANXA1 (hrANXA1) in the murine brain endothelial cell line bEnd.3. Also, ANXA1 was decreased in the bEnd.3 cells, the capillaries of 5XFAD mice, and the human serum of patients with AD. To find out the mechanism by which ANXA1 recovers the BBB integrity in AD, the RhoA-ROCK signaling pathway was examined in both Aβ42-treated bEnd.3 cells and the capillaries of 5XFAD mice as RhoA was activated in both cases. RhoA inhibitors alleviated Aβ42-induced BBB disruption and constitutively overexpressed RhoA-GTP (active form of RhoA) attenuated the protective effect of ANXA1. When pericytes were cocultured with bEnd.3 cells, Aβ42-induced RhoA activation of bEnd.3 cells was inhibited by the secretion of ANXA1 from pericytes. Taken together, our results suggest that ANXA1 restores Aβ42-induced BBB disruption through inhibition of RhoA-ROCK signaling pathway and we propose ANXA1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Jong-Chan
authors.initials: JC
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Baik
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Sun-Ho
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Haeng Jun
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Heesun
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Wonik
authors.initials: W
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Dong Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 110-799, Korea.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017305:Annexin A1 / Q000097:blood / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000633:toxicity*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000097:blood; D044067:Receptors, Lipoxin / Q000097:blood; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017305:Annexin A1; C105101:FPR2 protein, human; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: 5XFAD mice; Alzheimer's disease; Annexin A1; blood-brain barrier; endothelial cell; pericyte; β-amyloid