Open AccessAnnexin A1 restores Aβ 1‐42 ‐induced blood–brain barrier disruption through the inhibition of RhoA‐ ROCK signaling pathway
Author(s) -
Park JongChan,
Baik Sung Hoon,
Han SunHo,
Cho Hyun Jin,
Choi Hyunjung,
Kim Haeng Jun,
Choi Heesun,
Lee Wonik,
Kim Dong Kyu,
MookJung Inhee
Publication year - 2017
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12530
Subject(s) - rhoa , blood–brain barrier , microbiology and biotechnology , biology , annexin a2 , annexin a5 , signal transduction , annexin , pericyte , endothelial stem cell , central nervous system , endocrinology , flow cytometry , biochemistry , in vitro
Summary 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 ( ANXA 1), 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 ANXA 1 (hr ANXA 1) in the murine brain endothelial cell line bE nd.3. Also, ANXA 1 was decreased in the bE nd.3 cells, the capillaries of 5 XFAD mice, and the human serum of patients with AD . To find out the mechanism by which ANXA 1 recovers the BBB integrity in AD , the RhoA‐ ROCK signaling pathway was examined in both Aβ42‐treated bE nd.3 cells and the capillaries of 5 XFAD 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 ANXA 1. When pericytes were cocultured with bE nd.3 cells, Aβ42‐induced RhoA activation of bE nd.3 cells was inhibited by the secretion of ANXA 1 from pericytes. Taken together, our results suggest that ANXA 1 restores Aβ42‐induced BBB disruption through inhibition of RhoA‐ ROCK signaling pathway and we propose ANXA 1 as a therapeutic reagent, protecting against the breakdown of the BBB in AD.