Perlecan Domain V Increases Amyloid Clearance in Co‐Morbid VCID

Abstract

IntroductionVascular contributions to cognitive impairment and dementia (VCID) is a broad term that encompasses a spectrum of initial asymptomatic cerebrovascular changes (seen in small vessel disease and cerebral amyloid angiopathy) to the profound symptomatic damage following acute stroke(s). Besides aging, metabolic disorders such as type 2 diabetes complicate our understanding of underlying mechanisms. Cerebrovascular remodeling and angiogenesis may represent early compensatory changes to the reduced blood flow seen in VCID by increasing the proteolytic turnover of the surrounding extracellular matrix. We have demonstrated that one such extracellular matrix protein, perlecan, possesses a C terminal domain V (DV) protein that, upon cleavage from perlecan, greatly enhances brain angiogenesis.ObjectiveWe hypothesize that DV therapy can reduce pathological changes in the cerebrovasculature, an underlying component of VCID.MethodsDV'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.ResultsDV (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.ConclusionThese 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.Support or Funding InformationNIH RO1 N5089515‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.