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Relationships of brain cholesterol and cholesterol biosynthetic enzymes to Alzheimer's pathology and dementia in the CFAS population-derived neuropathology cohort.

Accepted version
Peer-reviewed

Type

Article

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Authors

Mistry, Hemant 
Richardson, Connor D 
Higginbottom, Adrian 
Ashford, Bridget 
Ahamed, Saif U 

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.

Description

Keywords

Alzheimer’s disease, Cholesterol, Cognitive Function and Ageing Study, Dementia, HMG-CoA reductase, Sterol regulatory element-binding proteins

Journal Title

Neurosci Res

Conference Name

Journal ISSN

0168-0102
1872-8111

Volume Title

Publisher

Elsevier BV
Sponsorship
Medical Research Council (G9901400)
Medical Research Council (G0900582)
Medical Research Council (G0601022/1)
Medical Research Council (G0900582/1)