Abstract WP558: Benefits of Perlecan Domain V in Diabetic Co-morbid Models of VCID

Abstract

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a major factor in the overall clinical burden of dementia. Besides aging, metabolic disorders such as type 2 diabetes complicate understanding of underlying mechanisms. Despite the complexity, we hypothesize that pathological changes in cerebrovascular extracellular matrix (ECM) are an underlying component of VCID that can be therapeutically targeted to reduce neurodegeneration and improve outcomes . One such ECM component, the terminal domain V (DV) of perlecan, greatly reduces amyloid toxicity and enhances angiogenic cerebrovascular remodeling. Methods: DV’s mechanism and therapeutic potential in facilitating Aβ clearance were examined in an ex vivo model of isolated mouse brain capillaries in normal and high glucose environments. We also determined the cerebrovascular changes in a comorbidity mouse model of VCID (diabetic APP/PS1 knock in (db/AD)) that is associated with hemorrhages, aneurysms, Aβ deposition, cognitive decline and increased mortality. Results: DV (300 and 600 nM) doubled the transport of fluorescently tagged hAβ1-42 over 24 hours from the bath (abluminal) to luminal side of the brain capillaries. One of Aβ’s known transport proteins, P-glycoprotein (P-gp), also increased in total protein expression and in transport activity in the presence of DV. At 3-6 months in db/AD mice, we observed a decrease in BBB proteins (claudin-5) indicating an altered cerebrovascular function correlating with DV expression increase during the asymptomatic angiogenic stage. At 9-12 months, cognitive changes were associated with altered cerebrovascular protein expression in PECAM, Collagen IV, and DV correlating with the aberrant two-photon vascular imaging, increased saccular aneurysms, and microhemorrhages. Conclusion: These data show that DV increases cerebrovascular Aβ clearance through P-gp. Increased DV expression correlates with early cerebrovascular changes induced by angiogenic-remodeling in a diabetic co-morbid mouse model of VCID. Lower DV expression is associated with aberrant vasculature that contribute to increased mortality, suggesting that DV ‘replacement therapy’ could represent a novel therapeutic for VCID.