Abstract P805: Inhibition of α5β1 Integrin as a Novel Therapeutic Approach in Experimental Vascular Dementia in Middle-Aged and Diabetic Mice

Abstract

Bilateral carotid artery stenosis (BCAS), a model of vascular dementia (VaD), causes cognitive impairment due to white matter injury and blood-brain barrier (BBB) disruption. Although risk factors for VaD such as Type-2 diabetes and aging are clinically relevant for therapeutic discovery, they are rarely studied. Recently, we determined that inhibition of brain α5β1 integrin with the peptide ATN-161 improves BBB stability and functional outcome after cerebral ischemia in mice. Also, after 14 days BCAS in mice, we showed increased brain α5β1 integrin expression which correlates with BBB disruption. We hypothesize that middle age and / or diabetes will intensify post-BCAS brain α5β1 integrin expression, contributing to worsened cerebrovascular pathology and cognitive decline, and that inhibition of α5β1 integrin with ATN-161 would reduce brain α5β1 integrin level, stabilize the BBB, attenuate brain-vascular pathology, and protect against VaD. Methods: BCAS was induced with titanium micro-coils (ID: 0.18 mm) in young and middle-aged C57B6/J (13-15 weeks old; n=57 and 57-63 weeks old; n=57, respectively) as well as in young 13-weeks old diabetic (B6.BKS(D)-Leprdb /- J, n=27; 35-56 g) and genotype control (B6.BKS(D)-Leprdb /+ J, n=27; 28-36 g) mice for 14, 32 and 60 days. After BCAS or sham surgery, mice were randomly assigned to ATN-161 (1 mg/kg, i.p., 3x /week) or saline groups. Functional outcome measures: Y-maze spontaneous alternation, novel object recognition and nesting tests were performed at baseline, post-BCAS days 14, 30, 48 & 60. Brain samples were assessed by immunofluorescence and western blot, for the expression of α5β1 integrin, tight junction proteins, as well as markers for white matter integrity, astrocyte and microglia activation. While the analysis of functional tests, brain histology and western blots are underway, we have thus-far determined that ATN-161 treatment reduces (p<0.01) BCAS-elevated brain α5β1 integrin to sham control levels and improves (p<0.001, compared to saline controls) Y-maze spontaneous alternation in young B6 mice after 14 days. We expect to demonstrate that inhibition of α5β1 with ATN-161 will improve cerebrovascular pathology and cognitive outcome following BCAS in middle-aged B6 and type-2 diabetic mice.