Modelling the role of APOE4 in blood-brain barrier dysfunctions with isogenic IPSC-derived brain microvascular endothelial cells and pericytes.

Abstract

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's Disease, and is known to affect the function of multiple neuronal and glial cell types. Recent research has suggested that blood-brain barrier (BBB) dysfunction is commonly observed among AD patients. However, it remains unclear whether and how APOE4 directly contributes to blood-brain barrier dysfunction. Isogenic iPSC lines with different APOE isoforms were differentiated into brain microvascular endothelial cell-like cells (BMECs) and neural crest-derived pericyte-like cells (PCs). Isogenic BMECs with different APOE isoforms were compared for their tight junction integrity, efflux transporter activity and amyloid clearance capabilities. Isogenic PCs with different APOE isoforms were compared for their APOE secretion levels and amyloid uptake capabilities. APOE4, APOE3 and APOE2 BMECs exhibited similar levels of tight junction protein expression, efflux transporter activities and trans-endothelial electrical resistance. However, we found that the presence of APOE ε4 protein, when compared with APOE ε2 and APOE ε3, led to reduced BMEC clearance of amyloid in a Transwell model. Compared to APOE3 and APOE2 PCs, APOE4 PCs demonstrated similar levels of APOE secretion, but had lower amyloid uptake capabilities. Our findings reveal that although APOE4 did not directly affect BMEC barrier properties in our hPSC-derived model, it plays a potentially important role in amyloid clearance by both BMECs and PCs.