Apolipoprotein E Status Mediates Pericyte Recruitment Mechanisms in the Presence of Excess Cholesterol

Abstract

AbstractBackgroundApolipoprotein E (APOE) is a multifunctional lipid transporter, involved in lipoprotein metabolism and mediation of cholesterol homeostasis. The E4 variant of APOE is a primary genetic risk factor for Alzheimer’s disease and has been associated with vascular conditions such as hyperlipidemia, hypercholesterolemia, atherosclerosis and coronary artery disease (CAD). The mechanisms underlying APOE involvement in blood‐brain barrier breakdown (BBB‐B) are not well understood. In vivo, in vitro and clinical models of E4 have all demonstrated distinct profiling of molecular factors involved in ECM remodelling ‐ such as upregulation of PDGF‐BB in plasma and downregulation of VEGF in CSF. Associations between PDGF‐BB and white matter disease burden have also been reported. Investigating how APOE contributes to BBB‐B, through its function as a lipid transporter, could be imperative to understanding the pathophysiology behind vascular contributions to dementia.MethodUsing data from the Alzheimer’s Disease Neuroimaging Institute (ADNI), we analyzed plasma concentrations PDGF‐BB, VEGF and serum‐derived lipoprotein cholesterol (measured as LDL.C/HDL.C) for 521 patients with differing APOE status (E3/E3: n = 216, E3/E4: n = 195, E4/E4: n = 60). The LDL.C/HDL.C ratio has been used to assess the prevalence lipoprotein particles in cardiovascular diseases, such as CAD and is a studied marker of lipoprotein expression.ResultOur findings revealed that APOE‐dependent upregulation of PDGF‐BB was predicted by blood derived measures of VEGF, LDL.C/HDL.C and an interaction effect of both. Interestingly, results of this model for the E3/E4 subgroup were non‐significant, instead we found that PDGF‐BB and VLDL.C/HDL.C predicted white matter hyperintensity burden on MRI. To further explore this relationship, biofluidic protein quantification and immunohistochemical staining of humanized APOE knock‐in mice (APOEε3/ε3, APOEε3/ε4 and APOEε4/ε4 ) are being conducted to characterize differences of peripheral vascular protein expression and brain‐specific PDGFRβ upregulation. In vitro modelling of pericyte‐endothelial cells is also being conducted to further investigate interactions of APOE‐dependent glio‐vascular signaling.ConclusionThis study provides additional support to previous reports that APOE4 contributes to impaired cerebrovascular function through mechanisms related to pericyte recruitment, vascular destabilization, and cognitive impairment. It may also provide additional insights for concepts which focus on APOE‐dependent cholesterol trafficking and lipid metabolism contribution to BBB destabilization.