AKT2 maintains brain endothelial claudin-5 expression and selective activation of IR/AKT2/FOXO1-signaling reverses barrier dysfunction. Issue 2 (February 2020)

• Record Type: Journal Article
• Authors: Beard, Richard S; Hoettels, Brian A; Meegan, Jamie E; Wertz, Travis S; Cha, Byeong J; Yang, Xiaoyuan; Oxford, Julia T; Wu, Mack H; Yuan, Sarah Y
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 40:Issue 2(2020)
• Page Start: 374
• Page End: 391
• Publication Date: 2020-02
• Subjects: AKT2 -- blood–brain barrier dysfunction -- claudin-5 -- FOXO1 -- endothelial IR signaling; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X18817512
• Languages: English
• ISSNs: 0271-678X

Abstract

Inflammation-induced blood–brain barrier (BBB) dysfunction and microvascular leakage are associated with a host of neurological disorders. The tight junction protein claudin-5 (CLDN5) is a crucial protein necessary for BBB integrity and maintenance. CLDN5 is negatively regulated by the transcriptional repressor FOXO1, whose activity increases during impaired insulin/AKT signaling. Owing to an incomplete understanding of the mechanisms that regulate CLDN5 expression in BBB maintenance and dysfunction, therapeutic interventions remain underdeveloped. Here, we show a novel isoform-specific function for AKT2 in maintenance of BBB integrity. We identified that AKT2 during homeostasis specifically regulates CLDN5-dependent barrier integrity in brain microvascular endothelial cells (BMVECs) and that intervention with a selective insulin-receptor (IR) agonist, demethylasterriquinone B1 (DMAQ-B1), rescued IL-1β-induced AKT2 inactivation, FOXO1 nuclear accumulation, and loss of CLDN5-dependent barrier integrity. Moreover, DMAQ-B1 attenuated preclinical CLDN5-dependent BBB dysfunction in mice subjected to experimental autoimmune encephalomyelitis. Taken together, the data suggest a regulatory role for IR/AKT2/FOXO1-signaling in CLDN5 expression and BBB integrity during neuroinflammation.