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Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons

Yuqing Feng Orcid Logo, Bismoy Mazumder, Tasuku Konno, Ernestine Hui, Marius Brockhoff, Valentina Davi, Meng Lu, Edward Ward, Amberley Stephens, Wenyue Dai, Ana Fernandez-Villegas, Giuliana Fusco, Mohsen Ali Asgari, Edward Avezov, Alfonso De Simone, Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Clemens Kaminski Orcid Logo, Gabriele Kaminski Schierle Orcid Logo, Mohsen Ali Asgari

bioRxiv

Swansea University Authors: Yuqin Wang Orcid Logo, William Griffiths Orcid Logo, Mohsen Ali Asgari

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DOI (Published version): 10.1101/2025.06.10.656594

Abstract

Disrupted cholesterol metabolism is increasingly recognised as a contributing factor in neurodegeneration; however, the specific effects of key brain-derived cholesterol metabolites, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC), remain poorly understood. Using human iPSC-derived...

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Published in: bioRxiv
Published: Cold Spring Harbor Laboratory
URI: https://cronfa.swan.ac.uk/Record/cronfa69790
first_indexed 2025-06-22T15:23:18Z
last_indexed 2025-12-05T17:59:45Z
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Using human iPSC-derived i3 cortical neurons, we demonstrate that both 24S-HC and 27-HC significantly impair neuronal calcium signalling by elevating resting calcium levels, reducing spike amplitude, and disrupting network synchrony. These functional deficits are accompanied by widespread organelle dysfunction. Both oxysterols induce mitochondrial fragmentation, decrease spare respiratory capacity, and impair lysosomal degradation. Notably, 27-HC uniquely triggers lysosomal swelling and membrane permeabilisation. Additional signs of cellular stress, including axonal swellings and elevated endoplasmic reticulum calcium levels, were also observed. Furthermore, both 24S-HC and 27-HC were found to directly interact with alpha-synuclein (aSyn), promoting its accumulation in cellular models. In contrast, cholesterol itself had minimal impact, highlighting the distinct toxicity of its hydroxylated metabolites. Together, these findings reveal a mechanistic link between oxysterol accumulation and neuronal dysfunction, supporting the hypothesis that elevated levels of 24S-HC and 27-HC, commonly observed in Parkinson&#x2019;s and Alzheimer&#x2019;s disease, may actively drive neurodegenerative processes. 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spelling 2025-12-04T14:12:37.9305740 v2 69790 2025-06-22 Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons c92729b58622f9fdf6a0e7d8f4ce5081 0000-0002-3063-3066 Yuqin Wang Yuqin Wang true false 3316b1d1b524be1831790933eed1c26e 0000-0002-4129-6616 William Griffiths William Griffiths true false 58bf75dabf1a8c8d58eda61b305d3cfd Mohsen Ali Asgari Mohsen Ali Asgari true false 2025-06-22 MEDS Disrupted cholesterol metabolism is increasingly recognised as a contributing factor in neurodegeneration; however, the specific effects of key brain-derived cholesterol metabolites, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC), remain poorly understood. Using human iPSC-derived i3 cortical neurons, we demonstrate that both 24S-HC and 27-HC significantly impair neuronal calcium signalling by elevating resting calcium levels, reducing spike amplitude, and disrupting network synchrony. These functional deficits are accompanied by widespread organelle dysfunction. Both oxysterols induce mitochondrial fragmentation, decrease spare respiratory capacity, and impair lysosomal degradation. Notably, 27-HC uniquely triggers lysosomal swelling and membrane permeabilisation. Additional signs of cellular stress, including axonal swellings and elevated endoplasmic reticulum calcium levels, were also observed. Furthermore, both 24S-HC and 27-HC were found to directly interact with alpha-synuclein (aSyn), promoting its accumulation in cellular models. In contrast, cholesterol itself had minimal impact, highlighting the distinct toxicity of its hydroxylated metabolites. Together, these findings reveal a mechanistic link between oxysterol accumulation and neuronal dysfunction, supporting the hypothesis that elevated levels of 24S-HC and 27-HC, commonly observed in Parkinson’s and Alzheimer’s disease, may actively drive neurodegenerative processes. Targeting oxysterol metabolism may therefore represent a promising therapeutic avenue for intervention in neurodegenerative disorders. Journal Article bioRxiv Cold Spring Harbor Laboratory 0 0 0 0001-01-01 10.1101/2025.06.10.656594 Preprint article before certification by peer review. COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Not Required MR/X012387/1 BB/S019588/1 Spatial Cholesterol Metabolism: A Mass Spectrometer for Better Diagnosis and Understanding of Disease Mass Spectrometry Based Lipidomics and Metabolomics to Drive Bioscience Discovery 2025-12-04T14:12:37.9305740 2025-06-22T16:05:33.7100124 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Yuqing Feng 0000-0002-4649-4857 1 Bismoy Mazumder 2 Tasuku Konno 3 Ernestine Hui 4 Marius Brockhoff 5 Valentina Davi 6 Meng Lu 7 Edward Ward 8 Amberley Stephens 9 Wenyue Dai 10 Ana Fernandez-Villegas 11 Giuliana Fusco 12 Mohsen Ali Asgari 13 Edward Avezov 14 Alfonso De Simone 15 Yuqin Wang 0000-0002-3063-3066 16 William Griffiths 0000-0002-4129-6616 17 Clemens Kaminski 0000-0002-5194-0962 18 Gabriele Kaminski Schierle 0000-0002-1843-2202 19 Mohsen Ali Asgari 20 327
title Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
spellingShingle Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
Yuqin Wang
William Griffiths
Mohsen Ali Asgari
title_short Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
title_full Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
title_fullStr Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
title_full_unstemmed Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
title_sort Brain cholesterol metabolites cause significant neurodegeneration in human iPSC-derived neurons
author_id_str_mv c92729b58622f9fdf6a0e7d8f4ce5081
3316b1d1b524be1831790933eed1c26e
58bf75dabf1a8c8d58eda61b305d3cfd
author_id_fullname_str_mv c92729b58622f9fdf6a0e7d8f4ce5081_***_Yuqin Wang
3316b1d1b524be1831790933eed1c26e_***_William Griffiths
58bf75dabf1a8c8d58eda61b305d3cfd_***_Mohsen Ali Asgari
author Yuqin Wang
William Griffiths
Mohsen Ali Asgari
author2 Yuqing Feng
Bismoy Mazumder
Tasuku Konno
Ernestine Hui
Marius Brockhoff
Valentina Davi
Meng Lu
Edward Ward
Amberley Stephens
Wenyue Dai
Ana Fernandez-Villegas
Giuliana Fusco
Mohsen Ali Asgari
Edward Avezov
Alfonso De Simone
Yuqin Wang
William Griffiths
Clemens Kaminski
Gabriele Kaminski Schierle
Mohsen Ali Asgari
format Journal article
container_title bioRxiv
institution Swansea University
doi_str_mv 10.1101/2025.06.10.656594
publisher Cold Spring Harbor Laboratory
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 0
active_str 0
description Disrupted cholesterol metabolism is increasingly recognised as a contributing factor in neurodegeneration; however, the specific effects of key brain-derived cholesterol metabolites, 24S-hydroxycholesterol (24S-HC) and 27-hydroxycholesterol (27-HC), remain poorly understood. Using human iPSC-derived i3 cortical neurons, we demonstrate that both 24S-HC and 27-HC significantly impair neuronal calcium signalling by elevating resting calcium levels, reducing spike amplitude, and disrupting network synchrony. These functional deficits are accompanied by widespread organelle dysfunction. Both oxysterols induce mitochondrial fragmentation, decrease spare respiratory capacity, and impair lysosomal degradation. Notably, 27-HC uniquely triggers lysosomal swelling and membrane permeabilisation. Additional signs of cellular stress, including axonal swellings and elevated endoplasmic reticulum calcium levels, were also observed. Furthermore, both 24S-HC and 27-HC were found to directly interact with alpha-synuclein (aSyn), promoting its accumulation in cellular models. In contrast, cholesterol itself had minimal impact, highlighting the distinct toxicity of its hydroxylated metabolites. Together, these findings reveal a mechanistic link between oxysterol accumulation and neuronal dysfunction, supporting the hypothesis that elevated levels of 24S-HC and 27-HC, commonly observed in Parkinson’s and Alzheimer’s disease, may actively drive neurodegenerative processes. Targeting oxysterol metabolism may therefore represent a promising therapeutic avenue for intervention in neurodegenerative disorders.
published_date 0001-01-01T05:29:06Z
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