Alzheimer’s disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound

Abstract Background The blood-brain barrier (BBB) has a major role in maintaining homeostasis of the brain. The primary function of the BBB is regulating the entry of molecules from the blood to the brain while protecting the brain from potentially harmful endogenous and exogenous substances. Transporters expressed in brain endothelial cells (BECs) mediate the uptake or efflux of compounds to and from the brain and they can also challenge the delivery of drugs into the brain for the treatment of brain disorders including Alzheimer’s disease (AD). AD is the most common form of dementia, however, currently there is limited understanding of the role of BBB transporters in AD-related BBB dysfunction. Methods We investigated differences in BBB transporter expression and activity in brain endothelial-like cells (iBECs) differentiated from induced pluripotent stem cells (iPSCs) obtained from people carrying the familial AD Presenilin 1 ( PSEN1 ) mutation ( PSEN1 exon 9 deletion; AD-iBECs), healthy controls (Ctrl-iBECs), and isogenic PSEN1 exon 9-corrected lines ( PSEN1 COR -iBECs). We first characterized the expression levels of 12 BBB transporters in AD-, Ctrl-, and isogenic iBECs to identify any AD specific differences. We then exposed the cells to focused ultrasound, in the absence (FUS only ) or presence of microbubbles (FUS +MB ), to examine whether the expression or activity of key transporters can be modulated by therapeutic ultrasound, a novel technique allowing for transient BBB opening. Results Our results identified differences in the expression of BBB transporters between AD-iBECs and control iBECs, suggesting disease-specific effects on transporter expression. Additionally, our results demonstrated FUS only and FUS +MB have the potential to modulate efflux transporter activity. Interestingly, AD-iBECs demonstrated significantly reduced PGP-mediated Aβ accumulation following FUS +MB , an effect not seen in Ctrl-iBECs, suggesting disease-related differences. Conclusions Our findings demonstrate that PSEN1 mutant AD-iBECs possess phenotypical differences compared to PSEN1 corrected and unrelated control iBECs in BBB transporter expression and function. Additionally, we show that FUS only and FUS +MB can modulate the BBB transporter expression and functional activity in iBECs, having potential implications on drug penetration and amyloid clearance. These findings highlight the differential responses of patient cells to FUS treatment, with patient-derived models likely providing an important tool for modelling of therapeutic effects of FUS.