Abstract 11467: ASK1 is Involved in Blood Brain Barrier Breakdown via Disruption of Endothelial Tight Junctions Thereby Contributing to Vascular Dementia
Background: Chronic cerebral ischemia in white matter (WM) causes vascular dementia. We reported that apoptosis signal-regulating kinase 1 (ASK1) is a key molecule involved in vascular endothelial dysfunction. We sought to prove that ASK1 is a key molecule in vascular dementia.
Methods: Chronic cerebral ischemia in WM including corpus callosum was induced in mice via bilateral common carotid artery stenosis (BCAS) with microcoils. [Study I] C57BL/6J mice (WT) and ASK1 deficient mice (ASK1 KO) were subdivided into sham and BCAS groups. [Study II] WT were treated with vehicle or p38 inhibitor, and subjected to BCAS. Cognitive function on the Y-maze test, WM lesions and glial cell activation in the corpus callosum were evaluated at 4 weeks post procedure. Extravasated Evans blue in the corpus callosum at 3 days post BCAS was measured under fluorescent microscopy to evaluate blood brain barrier (BBB) breakdown. [Study III] In vitro experiment, mouse cerebral endothelial cells were isolated to evaluate the effect of TNFα stimulation on the tight junction.
Results: [I] BCAS significantly and equally lowered cerebral blood flow of all groups. BCAS significantly caused cognitive decline, WM lesions and activation of astrocytes in WT but not in ASK1 KO. Cerebral mRNA levels of TNFα were increased in WT subjected to BCAS, but not in ASK1 KO. Phosphorylation of ASK1 in the brains of WT increased persistently after BCAS. Phosphorylation of p38 and TNFα expression increased in cerebral endothelial cells at the corpus callosum of WT after BCAS, but not in ASK1 KO. BCAS caused BBB disruption in the corpus callosum of WT, but not in ASK1 KO. [II] BCAS failed to disrupt the BBB in WT treated with the p38 inhibitor. Treatment with p38 inhibitor prevented cognitive decline, WM lesions, and glial cell activation, while it increased TNFα expression in WT subjected to BCAS. [III] In vitro, TNFα stimulation caused the disruption of the tight junction, such as claudin 5, in WT cerebral endothelial cells, but not in ASK1 KO.
Conclusions: ASK1 is involved in vascular dementia, through BBB breakdown via the disruption of the tight junction which is induced by the induction of TNFα in cerebral endothelial cells. ASK1 could be a promising novel therapeutic target molecule for vascular dementia.
- © 2012 by American Heart Association, Inc.