Abstract WP565: Inhibition of Alpha5Beta1 Integrin as a Novel Therapy for Experimental Vascular Dementia

Abstract

One of the prominent ways that ischemic brain injury expands is via disruption of the blood-brain barrier (BBB), allowing for increased edema and infiltration of inflammatory cells. Extracellular matrix proteins and their receptors are important contributors to the BBB. Notably, brain endothelial cell α5β1 integrin, a fibronectin receptor, is primarily expressed by brain endothelial cells during development, but increases following an injury such as ischemic stroke. We have previously shown that blockade of α5β1 integrin (via a small peptide ATN-161) after experimental stroke in mice leads to decreased infarct volumes, decreased leukocyte infiltration, and improved functional outcome. In addition, α5KO mice demonstrate improved BBB integrity and increased expression of the TJ protein claudin-5 following stroke compared to control mice. As disruption of the BBB is a key pathologic event in multiple cerebrovascular pathologies, we hypothesized that blockade of α5β1 integrin with ATN-161 could also be therapeutic in vascular contributions to cognitive impairment and dementia (VCID) , a prominent cause of dementia behind Alzheimer’s disease. VCID may occur, at least in part, as a result of chronic cerebral hypoperfusion, and eventually leads to white matter lesions, BBB disruptions and cognitive impairment. Here, we used the bilateral carotid artery stenosis (BCAS) model of chronic hypoperfusion, using 0.18 mm ID micro-coils wrapped around the carotid arteries of C57Bl/6 (male, 3 mo) mice to decrease, but not eliminate, blood flow to the brain. Interestingly, we observed a significant (p ≤ 0.001) increase in α5β1 integrin expression within 14 days post-stenosis and blockade of α5β1 integrin with ATN-161 (1 mg/kg; i.p.) significantly decreased α5β1 integrin expression. In addition, ATN-161 treatment significantly (p ≤ 0.01) decreased astrocyte activation (GFAP immunoreactivity) which occurs in the striatum following BCAS. Preliminary data also indicate improved cognitive outcome (Y-maze) with ATN-161 treatment as compared to controls. Collectively, these data indicate that α5β1 integrin may play a key role in a model of vascular dementia, and that inhibiting it with ATN-161 may stabilize the BBB and thereby slow or prevent disease progression.