Abstract
SummaryThe 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.
Highlights
The blood–brain barrier (BBB) is comprised of vascular endothelial cells, which are connected by tight junctions with a highly selective permeability by way of active transport mechanism (Pardridge, 2012)
To measure the BBB disruption in vitro and in vivo, we examined the levels of the tight junction proteins in bEnd.3 cells and performed IgG staining and an in vivo BBB permeability assay using sodium fluorescein (NaFI)
Immunocytochemistry with antibodies against ZO-1 and Claudin 5 showed fragmented patterns and less colocalization of both proteins in Ab42-treated bEnd.3 cells compared to the control (Fig. 1B, elliptic dotted line showed tight junctions and yellow signals showed the colocalization of ZO-1 and Claudin 5)
Summary
The blood–brain barrier (BBB) is comprised of vascular endothelial cells, which are connected by tight junctions with a highly selective permeability by way of active transport mechanism (Pardridge, 2012). Endothelial cells secrete platelet-derived growth factor-b (PDGFb) to recruit pericytes to survive against abnormal tumor vasculature (Chatterjee & Naik, 2012), and pericytes regulate endothelial cells by releasing cytokines (LaBarbera et al, 2015) In this way, the BBB has a critical role in maintaining homeostasis of the brain and separates the blood from the parenchyma of the central nervous system (CNS), as the major regulator between the brain and remainder of the body (Ballabh et al, 2004; Cristante et al, 2013) with the support of pericytes, which are generally known as key cells of the BBB maintenance
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