Altered brain endothelial cell phenotype from a familial Alzheimer mutation and its potential implications for amyloid clearance and drug delivery
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Date
2020
Authors
Oikari, L.E.
Pandit, R.
Stewart, R.
Cuní-López, C.
Quek, H.
Sutharsan, R.
Rantanen, L.M.
Oksanen, M.
Lehtonen, S.
de Boer, C.M.
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Journal article
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Stem Cell Reports, 2020; 14(5):924-939
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Lotta E.Oikari, Rucha Pandit, Romal Stewart, Carla Cuní-López, Hazel Quek, Ratneswary Sutharsan .. et al.
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Abstract
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.
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© 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/