Abstract WP295: Blocking the VCAM1-VLA4 Axis Prevents Cognitive Decline in a Mouse Model of Infarct-Induced Neurodegeneration

Abstract

Introduction: Infarct-induced neurodegeneration occurs chronically after stroke and can be prevented by inhibiting B cell influx. Vascular cell adhesion molecule 1 (VCAM1) facilitates immune cell diapedesis by binding very late antigen 4 (VLA4), and plasma levels are elevated after stroke in humans and mice. We hypothesized that chronic treatment with antibodies anti-VCAM1 or anti-VLA4 would reduce lymphocyte infiltration and prevent cognitive decline. Methods: Aged (10 month old) C57BL/6 male & female mice (N=9-10/group) underwent permanent middle cerebral artery occlusion and were dosed with anti-VCAM1, anti-VLA4, or control IgG every 3 days beginning 4 days after stroke for 10 weeks. Sham mice were also dosed with IgG. Barnes maze and Novel object were performed at -1, 1 and 6 weeks and single-cell RNA sequencing was performed on immune and endothelial cells at 10 weeks. Results: Blocking either VCAM1 or VLA4 reduced B cells 67% or 55%, respectively, compared to IgG treated stroked mice. Stroked mice treated with IgG developed a cognitive deficit in both Barnes maze and novel object by 6 weeks, while both anti-VCAM1 and anti-VLA4 treated mice performed comparably to sham animals in the Barnes maze (p=0.398; p=0.972, respectively). Similarly, sham IgG (p<0.0001), stroke anti-VCAM1 (p<0.0001) and VLA4 (p=0.0059) could all perform the novel object task. Single-cell sequencing of immune and brain endothelial cells demonstrated that most transcriptional changes occur in endothelial cells and not immune cells, and that anti-VCAM1 and anti-VLA4 induce similar transcriptional changes compared to control IgG after stroke. Specifically, both therapeutic antibodies restore heat shock protein expression ( Dnaja1, Hsp90ab1, Hspa8 ) and decrease inflammatory genes CD74 and IL1r1 . Transcriptional changes also reflect increased translation and Sox18 upregulation, consistent with angiogenesis. Conclusion: Blocking either VCAM1 or VLA4 prevents infarct-induced neurodegeneration in aged mice. Changes in endothelial cell transcription and decreased immune cells in the brain may both contribute to therapeutic effects. Together, these findings establish the VCAM1-VLA4 axis as a promising target to prevent infarct-induced neurodegeneration.