Stem Cell Reports
Volume 14, Issue 5, 12 May 2020, Pages 924-939
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Article
Altered Brain Endothelial Cell Phenotype from a Familial Alzheimer Mutation and Its Potential Implications for Amyloid Clearance and Drug Delivery

https://doi.org/10.1016/j.stemcr.2020.03.011Get rights and content
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Highlights

  • iBECs with familial AD mutation express altered levels of tight junction proteins

  • AD-iBECs exhibit altered efflux transporter expression and function to control iBECs

  • Focused ultrasound disrupts iBEC monolayer indicating effects of BBB opening

  • AD-iBECs respond differently to control iBECs to effects of focused ultrasound

Summary

The blood-brain barrier (BBB) presents a barrier for circulating factors, but simultaneously challenges drug delivery. How the BBB is altered in Alzheimer disease (AD) is not fully understood. To facilitate this analysis, we derived brain endothelial cells (iBECs) from human induced pluripotent stem cells (hiPSCs) of several patients carrying the familial AD PSEN1 mutation. We demonstrate that, compared with isogenic PSEN1 corrected and control iBECs, AD-iBECs exhibit altered tight and adherens junction protein expression as well as efflux properties. Furthermore, by applying focused ultrasound (FUS) that transiently opens the BBB and achieves multiple therapeutic effects in AD mouse models, we found an altered permeability to 3–5 kDa dextran as a model cargo and the amyloid-β (Aβ) peptide in AD-iBECs compared with control iBECs. This presents human-derived in vitro models of the BBB as a valuable tool to understand its role and properties in a disease context, with possible implications for drug delivery.

Keywords

Alzheimer disease
endothelial cells
blood-brain barrier
tight junctions
ultrasound therapy
induced pluripotent stem cells
induced brain endothelial cells
focused ultrasound

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8

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9

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