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Theranostics 2022; 12(16):6826-6847. doi:10.7150/thno.72685 This issue Cite

Research Paper

A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Joanna M. Wasielewska1,2, Juliana C. S. Chaves1, Rebecca L. Johnston3, Laura A. Milton1#, Damián Hernández4, Liyu Chen5, Jae Song5, Wendy Lee5, Gerhard Leinenga5, Rebecca M. Nisbet6, Alice Pébay4,7, Jürgen Götz5, Anthony R. White1,8*, Lotta E. Oikari1✉*

1. Cell & Molecular Biology Department, Mental Health and Neuroscience Program, QIMR Berghofer Medical Research Institute; Brisbane, QLD, Australia.
2. Faculty of Medicine, The University of Queensland; Brisbane, QLD, Australia.
3. Genetics & Computational Biology Department, QIMR Berghofer Medical Research Institute; Brisbane, QLD, Australia.
4. Department of Anatomy and Physiology, The University of Melbourne; Parkville, VIC, Australia.
5. Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland; Brisbane, QLD, Australia.
6. The Florey Institute of Neuroscience and Mental Health; Parkville, VIC, Australia.
7. Department of Surgery, Royal Melbourne Hospital, The University of Melbourne; Parkville, VIC, Australia.
8. School of Biomedical Sciences, Faculty of Medicine, The University of Queensland; Brisbane, QLD, Australia.
*These authors contributed equally to this work.
#Now located at: School of Mechanical, Medical and Process Engineering, Queensland University of Technology; Brisbane, QLD, Australia.

✉ Corresponding author: E-mail: Lotta.Oikariedu.au.

Citation:
Wasielewska JM, Chaves JCS, Johnston RL, Milton LA, Hernández D, Chen L, Song J, Lee W, Leinenga G, Nisbet RM, Pébay A, Götz J, White AR, Oikari LE. A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies. Theranostics 2022; 12(16):6826-6847. doi:10.7150/thno.72685. https://www.thno.org/v12p6826.htm
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Abstract

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Rationale: The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles (FUS+MB) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS+MB is safe, however, the effects of FUS+MB on human BBB cells, especially in the context of AD, remain sparsely investigated. In addition, there currently are no cell platforms to test for FUS+MB-mediated drug delivery.

Methods: Here we generated BBB cells (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high sporadic AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We established mono- and co-culture models of human sporadic AD and control BBB cells to investigate the effects of FUS+MB on BBB cell phenotype and to screen for the delivery of two potentially therapeutic AD antibodies, an Aducanumab-analogue (AduhelmTM; anti-amyloid-β) and a novel anti-Tau antibody, RNF5. We then developed a novel hydrogel-based 2.5D BBB model as a step towards a more physiologically relevant FUS+MB drug delivery platform.

Results: When compared to untreated cells, the delivery of Aducanumab-analogue and RNF5 was significantly increased (up to 1.73 fold), across the Transwell-based BBB models following FUS+MB treatment. Our results also demonstrated the safety of FUS+MB indicated by minimal changes in iBEC transcriptome as well as little or no changes in iBEC or iAstrocyte viability and inflammatory responses within the first 24 h post FUS+MB. Furthermore, we demonstrated successful iBEC barrier formation in our novel 2.5D hydrogel-based BBB model with significantly increased delivery (1.4 fold) of Aducanumab-analogue following FUS+MB.

Conclusion: Our results demonstrate a robust and reproducible approach to utilize patient cells for FUS+MB-mediated drug delivery screening in vitro. With such a cell platform for FUS+MB research previously not reported, it has the potential to identify novel FUS+MB-deliverable drugs as well as screen for cell- and patient-specific effects of FUS+MB, accelerating the use of FUS+MB as a therapeutic modality in AD.

Keywords: Alzheimer's disease, blood-brain barrier, focused ultrasound, drug delivery, Aduhelm

Citation styles

APA
Wasielewska, J.M., Chaves, J.C.S., Johnston, R.L., Milton, L.A., Hernández, D., Chen, L., Song, J., Lee, W., Leinenga, G., Nisbet, R.M., Pébay, A., Götz, J., White, A.R., Oikari, L.E. (2022). A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies. Theranostics, 12(16), 6826-6847. https://doi.org/10.7150/thno.72685.

ACS
Wasielewska, J.M.; Chaves, J.C.S.; Johnston, R.L.; Milton, L.A.; Hernández, D.; Chen, L.; Song, J.; Lee, W.; Leinenga, G.; Nisbet, R.M.; Pébay, A.; Götz, J.; White, A.R.; Oikari, L.E. A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies. Theranostics 2022, 12 (16), 6826-6847. DOI: 10.7150/thno.72685.

NLM
Wasielewska JM, Chaves JCS, Johnston RL, Milton LA, Hernández D, Chen L, Song J, Lee W, Leinenga G, Nisbet RM, Pébay A, Götz J, White AR, Oikari LE. A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies. Theranostics 2022; 12(16):6826-6847. doi:10.7150/thno.72685. https://www.thno.org/v12p6826.htm

CSE
Wasielewska JM, Chaves JCS, Johnston RL, Milton LA, Hernández D, Chen L, Song J, Lee W, Leinenga G, Nisbet RM, Pébay A, Götz J, White AR, Oikari LE. 2022. A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies. Theranostics. 12(16):6826-6847.

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