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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa61471
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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 (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.
College: Faculty of Medicine, Health and Life Sciences
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.
Issue: 665