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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)
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URI: https://cronfa.swan.ac.uk/Record/cronfa65566
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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 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.
College: Swansea University Medical School