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

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Chaves, Joanna M. Wasielewska, Carla Cuní-López, Laura M. Rantanen, Serine Lee, <a rel="Person" href="https://researchportal.helsinki.fi/en/persons/jari-eerik-koistinaho" class="link person"><span>Jari Koistinaho</span></a>, Anthony R. White, Lotta E. Oikari</div> <div class="rendering rendering_researchoutput rendering_researchoutput_associatesorganisationsportal rendering_contributiontojournal rendering_associatesorganisationsportal rendering_contributiontojournal_associatesorganisationsportal"><ul class="relations organisations"><li class="erillinen_laitos"><a rel="Organisation" href="https://researchportal.helsinki.fi/en/organisations/helsinki-institute-of-life-science-hilife" class="link"><span>Helsinki Institute of Life Science HiLIFE</span></a></li></ul></div> <div class="rendering rendering_researchoutput rendering_researchoutput_publicationcontenttyperendererportalng rendering_contributiontojournal rendering_publicationcontenttyperendererportalng rendering_contributiontojournal_publicationcontenttyperendererportalng"><p class="type"><span class="type_family">Research output<span class="type_family_sep">: </span></span><span class="type_classification_parent">Contribution to journal<span class="type_parent_sep"> › </span></span><span class="type_classification">Article</span><span class="type_classification"><span class="type_parent_sep"> › </span>Scientific</span><span class="type_classification"><span class="type_parent_sep"> › </span>peer-review</span></p></div> </div> </div> </div> <div class="subMenu"> <div class="content-profile-navigation"> <div class="container"> <nav role="navigation"> <ul class="has-overflow-navigation" role="menubar"> <li class="selected" role="none"> <a class="portal_link" role="menuitem" href="/en/publications/alzheimers-disease-brain-endothelial-like-cells-reveal-differenti"><span> <i class="icon icon-publication" aria-hidden="true"></i> <span class="label">Overview</span> </span></a> </li> </ul> </nav> </div> </div> </div> </section> <div id="main-content" class="page-section-content page-section-content-publications page-section-content-publications-view "> <section class="page-section content-relation-section"> <div class="container"> <div class="clearfix"> <div class="content-content publication-content"> <h2 class="subheader">Abstract</h2> <div class="rendering rendering_researchoutput rendering_researchoutput_abstractportal rendering_contributiontojournal rendering_abstractportal rendering_contributiontojournal_abstractportal"><div class="textblock"><p>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 (FUSonly) 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 FUSonly and FUS+MB, we investigated whether the expression or activity of key transporters could be modulated. Our findings demonstrate that PSEN1 mutant FAD (PSEN1AD) possess phenotypical differences compared to control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly 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.</p></div></div> <div class="rendering rendering_researchoutput rendering_researchoutput_detailsportal rendering_contributiontojournal rendering_detailsportal rendering_contributiontojournal_detailsportal"><div class="article"><table class="properties"><tbody><tr class="language"><th scope="row">Original language</th><td>English</td></tr><tr><th scope="row">Article number</th><td>e00299</td></tr><tr><th scope="row">Journal</th><td><a rel="Journal" href="#" class="link"><span>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</span></a></td></tr><tr><th scope="row">Volume</th><td>21</td></tr><tr><th scope="row">Issue number</th><td>1</td></tr><tr><th scope="row">Number of pages</th><td>15</td></tr><tr><th scope="row">ISSN</th><td>1933-7213</td></tr><tr class="digital_object_identifiers"><th scope="row">DOIs</th><td><ul class="relations digital_object_identifiers"><li><a onclick="window.open(this.href, '_blank','noopener,noreferrer'); return false;" href="https://doi.org/10.1016/j.neurot.2023.10.009" class="link"><span>https://doi.org/10.1016/j.neurot.2023.10.009</span></a> </li></ul></td></tr><tr class="status"><th scope="row">Publication status</th><td><span class="prefix">Published - </span><span class="date">1 Jan 2024</span></td></tr><tr class="assessmentType"><th scope="row">MoE publication type</th><td>A1 Journal article-refereed</td></tr></tbody></table></div></div> <div class="rendering rendering_researchoutput rendering_researchoutput_publicationbibliographicalnoteportalrenderer rendering_contributiontojournal rendering_publicationbibliographicalnoteportalrenderer rendering_contributiontojournal_publicationbibliographicalnoteportalrenderer"><h3 class="subheader">Bibliographical note</h3>Publisher Copyright:<br />Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.</div> <div class="rendering rendering_keywordable rendering_expertkeywordgrouspbytypeportal rendering_keywordable_expertkeywordgrouspbytypeportal"><div class="keyword-group"><h2 class="subheader">Fields of Science</h2><ul class="relations keywords"><li class="userdefined-keyword"><span>Alzheimer's disease</span></li><li class="userdefined-keyword"><span>Blood-brain barrier</span></li><li class="userdefined-keyword"><span>Drug transport</span></li><li class="userdefined-keyword"><span>Induced pluripotent stem cells</span></li><li class="userdefined-keyword"><span>Transporters</span></li><li class="userdefined-keyword"><span>Ultrasound therapy</span></li><li><span>3112 Neurosciences</span></li></ul></div></div> </div> <div class="content-sidebar publication-sidebar"> <h2 class="subheader">Access to Document</h2> <div class="rendering rendering_researchoutput rendering_researchoutput_publicationaccessrenderer rendering_contributiontojournal rendering_publicationaccessrenderer rendering_contributiontojournal_publicationaccessrenderer"><ul class="dois"><li class="open-access"><div class="doi"><a onclick="window.open(this.href, '_blank','noopener,noreferrer'); return false;" href="https://doi.org/10.1016/j.neurot.2023.10.009" class="link"><span>10.1016/j.neurot.2023.10.009</span></a></div></li></ul><ul class="documents"><li class="open-access"><div class="document"><a onclick="if (this.href) {window.open(this.href)}; return false;" href="/files/314184100/1-s2.0-S1878747923019372-main.pdf" class="link document-link"><span>1-s2.0-S1878747923019372-main</span></a><span class="meta">Final published version, 2.92 MB</span><span class="meta">Licence: <a onclick="window.open(this.href, '_blank','noopener,noreferrer'); return false;" href="http://creativecommons.org/licenses/by/4.0/" class="link">CC BY</a></span></div></li></ul></div> <div class="rendering rendering_researchoutput rendering_researchoutput_versioneddocumentspureportal rendering_contributiontojournal rendering_versioneddocumentspureportal rendering_contributiontojournal_versioneddocumentspureportal"><ul class="relations documents"></ul></div> </div> </div> </div> </section> <section class="page-section cite"> <div class="container"> <section class="publication-cite" aria-labelledby="publications-cite-title"> <h2 class="subheader" id="publications-cite-title">Cite this</h2> <ul class="tabs has-overflow-navigation" role="tablist" aria-label="Cite this"> <li class="selected" role="tab" id="tab-0" aria-controls="cite-apa" tabindex="-1" aria-selected="false" > APA </li> <li class="" role="tab" id="tab-1" aria-controls="cite-author" tabindex="-1" aria-selected="false" > Author </li> <li class="" role="tab" id="tab-2" aria-controls="cite-BIBTEX" tabindex="-1" aria-selected="false" > BIBTEX </li> <li class="" role="tab" id="tab-3" aria-controls="cite-harvard" tabindex="-1" aria-selected="false" > Harvard </li> <li class="" role="tab" id="tab-4" aria-controls="cite-standard" tabindex="-1" aria-selected="false" > Standard </li> <li class="" role="tab" id="tab-5" aria-controls="cite-RIS" tabindex="-1" aria-selected="false" > RIS </li> <li class="" role="tab" id="tab-6" aria-controls="cite-vancouver" tabindex="-1" aria-selected="false" > Vancouver </li> </ul> <div class="tab-container"> <div id="cite-apa" class="tab selected" role="tabpanel" aria-labelledby="tab-0" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_apa rendering_contributiontojournal rendering_apa rendering_contributiontojournal_apa">Chaves, J. C. S., Wasielewska, J. M., Cuní-López, C., Rantanen, L. M., Lee, S.<a rel="Person" href="https://researchportal.helsinki.fi/en/persons/jari-eerik-koistinaho" class="link"><span>, Koistinaho, J.</span></a>, White, A. R., & Oikari, L. E. (2024). <a rel="ContributionToJournal" href="https://researchportal.helsinki.fi/en/publications/alzheimers-disease-brain-endothelial-like-cells-reveal-differenti" class="link"><span>Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound</span></a>. <a rel="Journal" href="#" class="link"><span><em>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</em></span></a>, <em>21</em>(1), Article e00299. <a onclick="window.open(this.href, '_blank','noopener,noreferrer'); return false;" href="https://doi.org/10.1016/j.neurot.2023.10.009" class="link"><span>https://doi.org/10.1016/j.neurot.2023.10.009</span></a></div> </div> <div id="cite-author" class="tab " role="tabpanel" aria-labelledby="tab-1" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_author rendering_contributiontojournal rendering_author rendering_contributiontojournal_author">Chaves, Juliana C.S. ; Wasielewska, Joanna M. ; Cuní-López, Carla et al. / <a rel="ContributionToJournal" href="https://researchportal.helsinki.fi/en/publications/alzheimers-disease-brain-endothelial-like-cells-reveal-differenti" class="link"><span><strong>Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound</strong></span></a>. In: <a rel="Journal" href="#" class="link"><span>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</span></a>. 2024 ; Vol. 21, No. 1.</div> </div> <div id="cite-BIBTEX" class="tab " role="tabpanel" aria-labelledby="tab-2" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_bibtex rendering_contributiontojournal rendering_bibtex rendering_contributiontojournal_bibtex"><div>@article{54a9294cdbaa421cadd3270f79e2906e,</div><div> title = "Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound",</div><div> 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 (FUSonly) 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 FUSonly and FUS+MB, we investigated whether the expression or activity of key transporters could be modulated. Our findings demonstrate that PSEN1 mutant FAD (PSEN1AD) possess phenotypical differences compared to control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly 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.",</div><div> keywords = "Alzheimer's disease, Blood-brain barrier, Drug transport, Induced pluripotent stem cells, Transporters, Ultrasound therapy, 3112 Neurosciences",</div><div> author = "Chaves, {Juliana C.S.} and Wasielewska, {Joanna M.} and Carla Cun{\'i}-L{\'o}pez and Rantanen, {Laura M.} and Serine Lee and Jari Koistinaho and White, {Anthony R.} and Oikari, {Lotta E.}",</div><div> note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Author(s). Published by Elsevier Inc. All rights reserved.",</div><div> year = "2024",</div><div> month = jan,</div><div> day = "1",</div><div> doi = "10.1016/j.neurot.2023.10.009",</div><div> language = "English",</div><div> volume = "21",</div><div> journal = "Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics",</div><div> issn = "1933-7213",</div><div> publisher = "Elsevier Scientific Publ. Co",</div><div> number = "1",</div><p>}</p></div> </div> <div id="cite-harvard" class="tab " role="tabpanel" aria-labelledby="tab-3" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_harvard rendering_contributiontojournal rendering_harvard rendering_contributiontojournal_harvard">Chaves, JCS, Wasielewska, JM, Cuní-López, C, Rantanen, LM, Lee, S<a rel="Person" href="https://researchportal.helsinki.fi/en/persons/jari-eerik-koistinaho" class="link"><span>, Koistinaho, J</span></a>, White, AR & Oikari, LE 2024, '<a rel="ContributionToJournal" href="https://researchportal.helsinki.fi/en/publications/alzheimers-disease-brain-endothelial-like-cells-reveal-differenti" class="link harvard_title"><span>Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound</span></a>', <a rel="Journal" href="#" class="link"><span><em>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</em></span></a>, vol. 21, no. 1, e00299. <a onclick="window.open(this.href, '_blank','noopener,noreferrer'); return false;" href="https://doi.org/10.1016/j.neurot.2023.10.009" class="link"><span>https://doi.org/10.1016/j.neurot.2023.10.009</span></a></div> </div> <div id="cite-standard" class="tab " role="tabpanel" aria-labelledby="tab-4" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_standard rendering_contributiontojournal rendering_standard rendering_contributiontojournal_standard"><a rel="ContributionToJournal" href="https://researchportal.helsinki.fi/en/publications/alzheimers-disease-brain-endothelial-like-cells-reveal-differenti" class="link"><span><strong>Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound.</strong></span></a> / Chaves, Juliana C.S.; Wasielewska, Joanna M.; Cuní-López, Carla et al. <br />In: <a rel="Journal" href="#" class="link"><span>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</span></a>, Vol. 21, No. 1, e00299, 01.01.2024.<p class="type"><span class="type_family">Research output<span class="type_family_sep">: </span></span><span class="type_classification_parent">Contribution to journal<span class="type_parent_sep"> › </span></span><span class="type_classification">Article</span><span class="type_classification"><span class="type_parent_sep"> › </span>Scientific</span><span class="type_classification"><span class="type_parent_sep"> › </span>peer-review</span></p></div> </div> <div id="cite-RIS" class="tab " role="tabpanel" aria-labelledby="tab-5" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_ris rendering_contributiontojournal rendering_ris rendering_contributiontojournal_ris"><p>TY - JOUR</p><p>T1 - Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound</p><p>AU - Chaves, Juliana C.S.</p><p>AU - Wasielewska, Joanna M.</p><p>AU - Cuní-López, Carla</p><p>AU - Rantanen, Laura M.</p><p>AU - Lee, Serine</p><p>AU - Koistinaho, Jari</p><p>AU - White, Anthony R.</p><p>AU - Oikari, Lotta E.</p><p>N1 - Publisher Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.</p><p>PY - 2024/1/1</p><p>Y1 - 2024/1/1</p><p>N2 - 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 (FUSonly) 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 FUSonly and FUS+MB, we investigated whether the expression or activity of key transporters could be modulated. Our findings demonstrate that PSEN1 mutant FAD (PSEN1AD) possess phenotypical differences compared to control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly 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.</p><p>AB - 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 (FUSonly) 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 FUSonly and FUS+MB, we investigated whether the expression or activity of key transporters could be modulated. Our findings demonstrate that PSEN1 mutant FAD (PSEN1AD) possess phenotypical differences compared to control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly 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.</p><p>KW - Alzheimer's disease</p><p>KW - Blood-brain barrier</p><p>KW - Drug transport</p><p>KW - Induced pluripotent stem cells</p><p>KW - Transporters</p><p>KW - Ultrasound therapy</p><p>KW - 3112 Neurosciences</p><p>U2 - 10.1016/j.neurot.2023.10.009</p><p>DO - 10.1016/j.neurot.2023.10.009</p><p>M3 - Article</p><p>C2 - 38241156</p><p>AN - SCOPUS:85185218346</p><p>SN - 1933-7213</p><p>VL - 21</p><p>JO - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</p><p>JF - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</p><p>IS - 1</p><p>M1 - e00299</p><p>ER - </p></div> </div> <div id="cite-vancouver" class="tab " role="tabpanel" aria-labelledby="tab-6" tabindex="-1" aria-hidden="true"> <div class="rendering rendering_researchoutput rendering_researchoutput_vancouver rendering_contributiontojournal rendering_vancouver rendering_contributiontojournal_vancouver">Chaves JCS, Wasielewska JM, Cuní-López C, Rantanen LM, Lee S<a rel="Person" href="https://researchportal.helsinki.fi/en/persons/jari-eerik-koistinaho" class="link"><span>, Koistinaho J</span></a> et al. <span class="title"><a rel="ContributionToJournal" href="https://researchportal.helsinki.fi/en/publications/alzheimers-disease-brain-endothelial-like-cells-reveal-differenti" class="link"><span>Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound</span></a></span>. <a rel="Journal" href="#" class="link"><span>Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics</span></a>. 2024 Jan 1;21(1):e00299. doi: 10.1016/j.neurot.2023.10.009</div> </div> <script> $(function() { $(".tab-container .rendering a:not([href^='http://dx.doi.org'])").contents().unwrap(); 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Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound - University of Helsinki