Abstract

BACKGROUND: Ischemia is a well-established contributor to vascular dementia. Indeed, the most common pathology in people with dementia is mixed, and over half of patients diagnosed with AD have demonstrable vascular pathologies. Ischemia induces an immune response which triggers secondary neurodegeneration remote to the initial lesion, and consequent cognitive decline. Ischemia-triggered vascular dementia is dependent on B-lymphocytes driving chronic neuroinflammation in adult mice. However, vascular dementia is most common in the aged, and there are key differences in inflammatory responses with age. Vascular cell adhesion molecule 1 (VCAM1) is an endothelial protein that facilitates vascular-immune crosstalk via interaction with very late antigen-4 (VLA-4). Soluble VCAM1 is elevated in stroke, vascular dementia, and normal aging in both people and mice. In aging mice, anti-VCAM1 ameliorates age-induced neuroinflammation and cognitive impairment. Although the mechanism is unclear, this is likely mediated via changes in endothelial cell activation and secretion of pro-inflammatory mediators. Therefore, we hypothesized that acute anti-VCAM1 treatment would reduce microgliosis and astrogliosis, while delayed treatment would reduce B and T lymphocyte infiltration in a mouse model of ischemia-triggered vascular dementia.METHOD: Adult (3-month-old) or aged (10-month-old) C57BL/6J mice (n=10-15/group) underwent permanent distal middle cerebral artery occlusion. Mice were dosed with anti-VCAM1 antibody either 4 hours or 4 days post-ischemia, and then sacrificed at 72 hours, 3 weeks or 6 weeks post-ischemia. Microgliosis and astrogliosis were quantified as percent area immunostained in the lesion border by CD68 and GFAP, respectively. B and T cell infiltration were quantified as percent lesion immunostained by B220, and CD3+ cells in the ischemic lesion, respectively.RESULT: Acute treatment reduced microgliosis 30% (p=0.0476) and astrogliosis 39% (p<0.03). In adults, delayed anti-VCAM1 significantly reduced B and T cell infiltration approximately 25% (p=0.0015) and 50% (p=0.0192), respectively. Similarly, in aged mice, delayed anti-VCAM1 significantly reduced B and T cell infiltration approximately 50% (p=0.0037) and 30% (p=0.0036), respectively. In contrast, early anti-VCAM1 had little or no effect on B or T cell infiltration.CONCLUSION: Together, these findings establish VCAM1 as a possible therapeutic target to ameliorate ischemia-induced neuroinflammation and consequent cognitive decline in a mouse model of vascular dementia.

View details for DOI 10.1002/alz.053849

View details for PubMedID 35108898