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Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development

Hazem Ahmed Orcid Logo, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Allan I Levey, Irina Pikuleva Orcid Logo, Steven H Liang, Ahmed Haider Orcid Logo

Brain

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

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DOI (Published version): 10.1093/brain/awae028

Abstract

Cholesterol homeostasis is impaired in Alzheimer’s disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neurona...

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Published in: Brain
ISSN: 0006-8950 1460-2156
Published: Oxford University Press (OUP) 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa65566
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spelling v2 65566 2024-02-04 Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 2024-02-04 BMS Cholesterol homeostasis is impaired in Alzheimer’s disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of AD. Indeed, neuronal cholesterol was linked to the formation of amyloid-β (Aβ) and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Further, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with positron emission tomography, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in AD patients – with the ultimate aim to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in AD. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in AD patients. Journal Article Brain 0 Oxford University Press (OUP) 0006-8950 1460-2156 brain cholesterol homeostasis, Alzheimer’s disease, cholesterol lowering therapy, translational molecular imaging, cytochrome P450 46A1 (CYP46A1) 1 2 2024 2024-02-01 10.1093/brain/awae028 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Not Required 2024-04-07T13:01:19.1960416 2024-02-04T14:43:03.4590648 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Hazem Ahmed 0000-0001-7047-5202 1 Yuqin Wang 0000-0002-3063-3066 2 William Griffiths 0000-0002-4129-6616 3 Allan I Levey 4 Irina Pikuleva 0000-0001-9742-6232 5 Steven H Liang 6 Ahmed Haider 0000-0002-5204-4473 7 65566__29511__df02c4a1a6b844d8a511cc5437720fc9.pdf awae028.pdf 2024-02-04T14:54:09.2611976 Output 868509 application/pdf Accepted Manuscript true For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. true eng https://creativecommons.org/licenses/by/4.0/
title Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
spellingShingle Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
Yuqin Wang
William Griffiths
title_short Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
title_full Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
title_fullStr Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
title_full_unstemmed Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
title_sort Brain cholesterol and Alzheimer’s disease: challenges and opportunities in probe and drug development
author_id_str_mv c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
author_id_fullname_str_mv c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
author Yuqin Wang
William Griffiths
author2 Hazem Ahmed
Yuqin Wang
William Griffiths
Allan I Levey
Irina Pikuleva
Steven H Liang
Ahmed Haider
format Journal article
container_title Brain
container_volume 0
publishDate 2024
institution Swansea University
issn 0006-8950
1460-2156
doi_str_mv 10.1093/brain/awae028
publisher Oxford University Press (OUP)
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Cholesterol homeostasis is impaired in Alzheimer’s disease (AD), however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of AD. Indeed, neuronal cholesterol was linked to the formation of amyloid-β (Aβ) and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Further, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with positron emission tomography, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in AD patients – with the ultimate aim to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in AD. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in AD patients.
published_date 2024-02-01T13:01:16Z
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