Relationships of Brain Cholesterol and Cholesterol Biosynthetic Enzymes to Alzheimer’s Pathology and Dementia in the CFAS Population-Derived Neuropathology Cohort

Mistry, Hemant; Richardson, Connor D.; Higginbottom, Adrian; Ashford, Bridget; Ahamed, Saif U.; Moore, Zoe; Matthews, Fiona E.; Brayne, Carol; Simpson, Julie E.; Wharton, Stephen B.

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.

Citation

Mistry, H., Richardson, C. D., Higginbottom, A., Ashford, B., Ahamed, S. U., Moore, Z., Matthews, F. E., Brayne, C., Simpson, J. E., & Wharton, S. B. (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, Article 22-33. https://doi.org/10.1016/j.neures.2024.01.003

• Journal Article Type: Article
• Acceptance Date: Jan 17, 2024
• Online Publication Date: Jan 24, 2024
• Publication Date: Jul 1, 2024
• Deposit Date: Jan 28, 2024
• Publicly Available Date: Jun 26, 2024
• Journal: Neuroscience Research
• Print ISSN: 0168-0102
• Electronic ISSN: 1872-8111
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 204
• Article Number: 22-33
• DOI: https://doi.org/10.1016/j.neures.2024.01.003
• Keywords: Cholesterol; HMG-CoA reductase; Sterol regulatory element-binding proteins; Dementia; Alzheimer’s disease; Cognitive Function and Ageing Study
• Public URL: https://hull-repository.worktribe.com/output/4529373