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Assessment of cholesterol homeostasis in the living human brain

Ahmed Haider Orcid Logo, Chunyu Zhao Orcid Logo, Lu Wang Orcid Logo, Zhiwei Xiao, Jian Rong, Xiaotian Xia Orcid Logo, Zhen Chen Orcid Logo, Stefanie K. Pfister Orcid Logo, Natalia Mast Orcid Logo, Eylan Yutuc Orcid Logo, Jiahui Chen Orcid Logo, Yinlong Li Orcid Logo, Tuo Shao, Geoffrey I. Warnock, Alyaa Dawoud Orcid Logo, Theresa R. Connors Orcid Logo, Derek H. Oakley Orcid Logo, Huiyi Wei, Jinghao Wang, Zhihua Zheng Orcid Logo, Hao Xu, April T. Davenport, James B. Daunais, Richard S. Van, Yihan Shao, Yuqin Wang Orcid Logo, Ming-Rong Zhang, Catherine Gebhard Orcid Logo, Irina Pikuleva Orcid Logo, Allan I. Levey Orcid Logo, William Griffiths Orcid Logo, Steven H. Liang Orcid Logo

Science Translational Medicine, Volume: 14, Issue: 665

Swansea University Authors: Eylan Yutuc Orcid Logo, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo

Abstract

Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CY...

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Published in: Science Translational Medicine
ISSN: 1946-6234 1946-6242
Published: American Association for the Advancement of Science (AAAS) 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa61471
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Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a non-invasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly impact disease diagnosis and treatment options using targeted therapies. Here we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer. 18F-CHL-2205(18F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species post-mortem analyses of specimens from rodents, non-human primates and humans. Proof-of-concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Further, our clinical observations point towards a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for non-invasive assessment of brain cholesterol homeostasis in the clinic.</abstract><type>Journal Article</type><journal>Science Translational Medicine</journal><volume>14</volume><journalNumber>665</journalNumber><paginationStart/><paginationEnd/><publisher>American Association for the Advancement of Science (AAAS)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1946-6234</issnPrint><issnElectronic>1946-6242</issnElectronic><keywords/><publishedDay>5</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-10-05</publishedDate><doi>10.1126/scitranslmed.adc9967</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>NIH (AA028007 to JBD, AG070060 and AG074218 to SHL); BBSRC (BB/S019588/1 and BB/N015932/1 to WJG, BB/L001942/1 to YW), and the European Union, through European Structural Funds (ESF), as part of the Welsh Government funded Academic Expertise for Business project (to WJG and YW); the Swiss National Science Foundation to AH, and Emory Radiology Chair Fund to SHL.</funders><projectreference/><lastEdited>2023-09-13T16:54:43.0088716</lastEdited><Created>2022-10-07T09:12:40.9779539</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Ahmed</firstname><surname>Haider</surname><orcid>0000-0002-5204-4473</orcid><order>1</order></author><author><firstname>Chunyu</firstname><surname>Zhao</surname><orcid>0000-0003-0168-2130</orcid><order>2</order></author><author><firstname>Lu</firstname><surname>Wang</surname><orcid>0000-0002-8049-1991</orcid><order>3</order></author><author><firstname>Zhiwei</firstname><surname>Xiao</surname><order>4</order></author><author><firstname>Jian</firstname><surname>Rong</surname><order>5</order></author><author><firstname>Xiaotian</firstname><surname>Xia</surname><orcid>0000-0002-3917-4361</orcid><order>6</order></author><author><firstname>Zhen</firstname><surname>Chen</surname><orcid>0000-0002-6289-4332</orcid><order>7</order></author><author><firstname>Stefanie K.</firstname><surname>Pfister</surname><orcid>0000-0002-1394-3716</orcid><order>8</order></author><author><firstname>Natalia</firstname><surname>Mast</surname><orcid>0000-0001-6427-640x</orcid><order>9</order></author><author><firstname>Eylan</firstname><surname>Yutuc</surname><orcid>0000-0001-9971-1950</orcid><order>10</order></author><author><firstname>Jiahui</firstname><surname>Chen</surname><orcid>0000-0001-9186-1110</orcid><order>11</order></author><author><firstname>Yinlong</firstname><surname>Li</surname><orcid>0000-0002-8864-1712</orcid><order>12</order></author><author><firstname>Tuo</firstname><surname>Shao</surname><order>13</order></author><author><firstname>Geoffrey I.</firstname><surname>Warnock</surname><order>14</order></author><author><firstname>Alyaa</firstname><surname>Dawoud</surname><orcid>0000-0002-8140-1070</orcid><order>15</order></author><author><firstname>Theresa R.</firstname><surname>Connors</surname><orcid>0000-0002-9706-8217</orcid><order>16</order></author><author><firstname>Derek H.</firstname><surname>Oakley</surname><orcid>0000-0002-6998-9510</orcid><order>17</order></author><author><firstname>Huiyi</firstname><surname>Wei</surname><order>18</order></author><author><firstname>Jinghao</firstname><surname>Wang</surname><order>19</order></author><author><firstname>Zhihua</firstname><surname>Zheng</surname><orcid>0000-0001-9312-5846</orcid><order>20</order></author><author><firstname>Hao</firstname><surname>Xu</surname><order>21</order></author><author><firstname>April T.</firstname><surname>Davenport</surname><order>22</order></author><author><firstname>James B.</firstname><surname>Daunais</surname><order>23</order></author><author><firstname>Richard S.</firstname><surname>Van</surname><order>24</order></author><author><firstname>Yihan</firstname><surname>Shao</surname><order>25</order></author><author><firstname>Yuqin</firstname><surname>Wang</surname><orcid>0000-0002-3063-3066</orcid><order>26</order></author><author><firstname>Ming-Rong</firstname><surname>Zhang</surname><order>27</order></author><author><firstname>Catherine</firstname><surname>Gebhard</surname><orcid>0000-0001-7240-5822</orcid><order>28</order></author><author><firstname>Irina</firstname><surname>Pikuleva</surname><orcid>0000-0001-9742-6232</orcid><order>29</order></author><author><firstname>Allan I.</firstname><surname>Levey</surname><orcid>0000-0002-3153-502x</orcid><order>30</order></author><author><firstname>William</firstname><surname>Griffiths</surname><orcid>0000-0002-4129-6616</orcid><order>31</order></author><author><firstname>Steven H.</firstname><surname>Liang</surname><orcid>0000-0003-1413-6315</orcid><order>32</order></author></authors><documents><document><filename>61471__25549__a4b30c0a412947238a0695831704bbe3.pdf</filename><originalFilename>61471.pdf</originalFilename><uploaded>2022-10-24T09:52:14.8532878</uploaded><type>Output</type><contentLength>243252</contentLength><contentType>application/pdf</contentType><version>Accepted Manuscript</version><cronfaStatus>true</cronfaStatus><copyrightCorrect>true</copyrightCorrect><language>eng</language></document><document><filename>61471__25550__194c2fd4221644c48de00e9aeb160875.pdf</filename><originalFilename>61471_SupplementalMaterial_v6.pdf</originalFilename><uploaded>2022-10-24T09:52:36.8473903</uploaded><type>Output</type><contentLength>860047</contentLength><contentType>application/pdf</contentType><version>Supplemental material</version><cronfaStatus>true</cronfaStatus><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling v2 61471 2022-10-07 Assessment of cholesterol homeostasis in the living human brain 99332f073ce913a9b7d8b6441b17516d 0000-0001-9971-1950 Eylan Yutuc Eylan Yutuc true false c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2022-10-07 BMS Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a non-invasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly impact disease diagnosis and treatment options using targeted therapies. Here we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer. 18F-CHL-2205(18F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species post-mortem analyses of specimens from rodents, non-human primates and humans. Proof-of-concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Further, our clinical observations point towards a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for non-invasive assessment of brain cholesterol homeostasis in the clinic. Journal Article Science Translational Medicine 14 665 American Association for the Advancement of Science (AAAS) 1946-6234 1946-6242 5 10 2022 2022-10-05 10.1126/scitranslmed.adc9967 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University NIH (AA028007 to JBD, AG070060 and AG074218 to SHL); BBSRC (BB/S019588/1 and BB/N015932/1 to WJG, BB/L001942/1 to YW), and the European Union, through European Structural Funds (ESF), as part of the Welsh Government funded Academic Expertise for Business project (to WJG and YW); the Swiss National Science Foundation to AH, and Emory Radiology Chair Fund to SHL. 2023-09-13T16:54:43.0088716 2022-10-07T09:12:40.9779539 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ahmed Haider 0000-0002-5204-4473 1 Chunyu Zhao 0000-0003-0168-2130 2 Lu Wang 0000-0002-8049-1991 3 Zhiwei Xiao 4 Jian Rong 5 Xiaotian Xia 0000-0002-3917-4361 6 Zhen Chen 0000-0002-6289-4332 7 Stefanie K. Pfister 0000-0002-1394-3716 8 Natalia Mast 0000-0001-6427-640x 9 Eylan Yutuc 0000-0001-9971-1950 10 Jiahui Chen 0000-0001-9186-1110 11 Yinlong Li 0000-0002-8864-1712 12 Tuo Shao 13 Geoffrey I. Warnock 14 Alyaa Dawoud 0000-0002-8140-1070 15 Theresa R. Connors 0000-0002-9706-8217 16 Derek H. Oakley 0000-0002-6998-9510 17 Huiyi Wei 18 Jinghao Wang 19 Zhihua Zheng 0000-0001-9312-5846 20 Hao Xu 21 April T. Davenport 22 James B. Daunais 23 Richard S. Van 24 Yihan Shao 25 Yuqin Wang 0000-0002-3063-3066 26 Ming-Rong Zhang 27 Catherine Gebhard 0000-0001-7240-5822 28 Irina Pikuleva 0000-0001-9742-6232 29 Allan I. Levey 0000-0002-3153-502x 30 William Griffiths 0000-0002-4129-6616 31 Steven H. Liang 0000-0003-1413-6315 32 61471__25549__a4b30c0a412947238a0695831704bbe3.pdf 61471.pdf 2022-10-24T09:52:14.8532878 Output 243252 application/pdf Accepted Manuscript true true eng 61471__25550__194c2fd4221644c48de00e9aeb160875.pdf 61471_SupplementalMaterial_v6.pdf 2022-10-24T09:52:36.8473903 Output 860047 application/pdf Supplemental material true true eng
title Assessment of cholesterol homeostasis in the living human brain
spellingShingle Assessment of cholesterol homeostasis in the living human brain
Eylan Yutuc
Yuqin Wang
William Griffiths
title_short Assessment of cholesterol homeostasis in the living human brain
title_full Assessment of cholesterol homeostasis in the living human brain
title_fullStr Assessment of cholesterol homeostasis in the living human brain
title_full_unstemmed Assessment of cholesterol homeostasis in the living human brain
title_sort Assessment of cholesterol homeostasis in the living human brain
author_id_str_mv 99332f073ce913a9b7d8b6441b17516d
c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv 99332f073ce913a9b7d8b6441b17516d_***_Eylan Yutuc
c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author Eylan Yutuc
Yuqin Wang
William Griffiths
author2 Ahmed Haider
Chunyu Zhao
Lu Wang
Zhiwei Xiao
Jian Rong
Xiaotian Xia
Zhen Chen
Stefanie K. Pfister
Natalia Mast
Eylan Yutuc
Jiahui Chen
Yinlong Li
Tuo Shao
Geoffrey I. Warnock
Alyaa Dawoud
Theresa R. Connors
Derek H. Oakley
Huiyi Wei
Jinghao Wang
Zhihua Zheng
Hao Xu
April T. Davenport
James B. Daunais
Richard S. Van
Yihan Shao
Yuqin Wang
Ming-Rong Zhang
Catherine Gebhard
Irina Pikuleva
Allan I. Levey
William Griffiths
Steven H. Liang
format Journal article
container_title Science Translational Medicine
container_volume 14
container_issue 665
publishDate 2022
institution Swansea University
issn 1946-6234
1946-6242
doi_str_mv 10.1126/scitranslmed.adc9967
publisher American Association for the Advancement of Science (AAAS)
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Alterations in brain cholesterol homeostasis have been broadly implicated in neurological disorders. Notwithstanding the complexity by which cholesterol biology is governed in the mammalian brain, excess neuronal cholesterol is primarily eliminated by metabolic clearance via cytochrome P450 46A1 (CYP46A1). No methods are currently available for visualizing cholesterol metabolism in the living human brain; therefore, a non-invasive technology that quantitatively measures the extent of brain cholesterol metabolism via CYP46A1 could broadly impact disease diagnosis and treatment options using targeted therapies. Here we describe the development and testing of a CYP46A1-targeted positron emission tomography (PET) tracer. 18F-CHL-2205(18F-Cholestify). Our data show that PET imaging readouts correlate with CYP46A1 protein expression and with the extent to which cholesterol is metabolized in the brain, as assessed by cross-species post-mortem analyses of specimens from rodents, non-human primates and humans. Proof-of-concept of in vivo efficacy is provided in the well-established 3xTg-AD murine model of Alzheimer’s disease (AD), where we show that the probe is sensitive to differences in brain cholesterol metabolism between 3xTg-AD mice and control animals. Further, our clinical observations point towards a considerably higher baseline brain cholesterol clearance via CYP46A1 in women, as compared to age-matched men. These findings illustrate the vast potential of assessing brain cholesterol metabolism using PET and establish PET as a sensitive tool for non-invasive assessment of brain cholesterol homeostasis in the clinic.
published_date 2022-10-05T16:54:45Z
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