Mistry, H., Richardson, C.D., Higginbottom, A. orcid.org/0000-0002-3246-6695 et al. (7 more authors) (2024) Relationships of brain cholesterol and cholesterol biosynthetic enzymes to Alzheimer’s pathology and dementia in the CFAS population-derived neuropathology cohort. Neuroscience Research, 204. pp. 22-33. ISSN 0168-0102
Abstract
Altered cholesterol metabolism is implicated in brain ageing and Alzheimer's disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer's disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Alzheimer’s disease; Cholesterol; Cognitive Function and Ageing Study; Dementia; HMG-CoA reductase; Sterol regulatory element-binding proteins; Humans; Cholesterol; Male; Sterol Regulatory Element Binding Protein 2; Hydroxymethylglutaryl CoA Reductases; Female; Alzheimer Disease; Aged; Dementia; Aged, 80 and over; Brain; Cohort Studies; Neurons; Cholesterol 24-Hydroxylase; Astrocytes |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Funding Information: | Funder Grant number Medical Research Council G0900582 Medical Research Council G9901400 MEDICAL RESEARCH COUNCIL G0900582/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 01 Nov 2024 10:00 |
Last Modified: | 01 Nov 2024 10:00 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.neures.2024.01.003 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:219110 |
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