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

Juliana C S Chaves; Joanna M Wasielewska; Carla Cuní-López; Laura M Rantanen; Serine Lee; Jari Koistinaho; Anthony R White; Lotta E Oikari

doi:10.1016/j.neurot.2023.10.009

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

Neurotherapeutics. 2024 Jan;21(1):e00299. doi: 10.1016/j.neurot.2023.10.009. Epub 2023 Dec 19.

Authors

Juliana C S Chaves¹, Joanna M Wasielewska², Carla Cuní-López², Laura M Rantanen¹, Serine Lee³, Jari Koistinaho⁴, Anthony R White⁵, Lotta E Oikari⁶

Affiliations

¹ Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QUT, Brisbane, QLD, Australia.
² Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
³ Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁴ A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Neuroscience Center, Kuopio, Finland; Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
⁵ Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QUT, Brisbane, QLD, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
⁶ Mental Health and Neuroscience, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Electronic address: Lotta.Oikari@qimrberghofer.edu.au.

Abstract

The blood-brain barrier (BBB) has a key function in maintaining homeostasis in the brain, partly modulated by transporters, which are highly expressed in brain endothelial cells (BECs). Transporters mediate the uptake or efflux of compounds to and from the brain and they can also challenge the delivery of drugs for the treatment of Alzheimer's disease (AD). Currently there is a limited understanding of changes in BBB transporters in AD. To investigate this, we generated brain endothelial-like cells (iBECs) from induced pluripotent stem cells (iPSCs) with familial AD (FAD) Presenilin 1 (PSEN1) mutation and identified AD-specific differences in transporter expression compared to control (ctrl) iBECs. We first characterized the expression levels of 12 BBB transporters in AD-, Ctrl-, and isogenic (PSEN1 corrected) iBECs to identify any AD specific differences. We then exposed the cells to focused ultrasound (FUS) in the absence (FUS^only) or presence of microbubbles (MB) (FUS^+MB), which is a novel therapeutic method that can be used to transiently open the BBB to increase drug delivery into the brain, however its effects on BBB transporter expression are largely unknown. Following FUS^only and FUS^+MB, we investigated whether the expression or activity of key transporters could be modulated. Our findings demonstrate that PSEN1 mutant FAD (PSEN1^AD) possess phenotypical differences compared to control iBECs in BBB transporter expression and function. Additionally, we show that FUS^only and FUS^+MB can modulate 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 therapeutic effects of FUS.

Keywords: Alzheimer's disease; Blood-brain barrier; Drug transport; Induced pluripotent stem cells; Transporters; Ultrasound therapy.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / therapy
Blood-Brain Barrier
Brain / metabolism
Endothelial Cells / metabolism
Humans
Membrane Transport Proteins / metabolism
Pharmaceutical Preparations / metabolism

Substances

Pharmaceutical Preparations
Membrane Transport Proteins