Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology.

TitleEffects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer's Disease Pathology.
Publication TypeJournal Article
Year of Publication2016
AuthorsLeduc V, Théroux L, Dea D, Dufour R, Poirier J
JournalJ Mol Neurosci
Volume58
Issue1
Pagination109-19
Date Published2016 Jan
ISSN1559-1166
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Case-Control Studies, Cerebellum, Female, Frontal Lobe, Humans, Hydroxymethylglutaryl CoA Reductases, Male, Middle Aged, Peptide Fragments, Polymorphism, Single Nucleotide, RNA, Messenger, tau Proteins
Abstract

3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is a cholesterol-regulating gene with statin relevance. rs3846662 being involved in regulation of HMGCR alternative splicing, we explored its impact on HMGCR messenger RNA (mRNA) and protein levels in the brain and the associations between those levels and levels of Alzheimer's disease pathological markers. We used brain samples derived from a cohort of 33 non-demented controls and 90 Alzheimer's disease autopsied-confirmed cases. HMGCR mRNA levels were determined in the frontal cortex (n = 114) and cerebellum (n = 110) using Taqman-qPCR, and HMGCR protein levels were determined in the frontal cortex (n = 117) using a commercial enzyme immunoassay. While densities of neurofibrillary tangles and senile plaques were determined in the frontal cortex (n = 74), total tau, phosphorylated Tau, and beta-amyloid 1-42 levels were determined in the frontal cortex (n = 94) and cerebellum (n = 91) using commercial enzyme immunoassays. Despite an increase in full-length HMGCR mRNA ratio in the frontal cortex of women carrying the AA genotype, there were no associations between rs3846662 and HMGCR mRNA or protein levels. An increased Δ13 HMGCR mRNA ratio was associated with increased levels of HMGCR proteins and neurofibrillary tangles in the frontal cortex but with reduced beta-amyloid 1-42 levels in the cerebellum, suggesting a brain cell type- or a disease progression-dependent association.

DOI10.1007/s12031-015-0666-7
Alternate JournalJ. Mol. Neurosci.
PubMed ID26541602
PubMed Central IDPMC5138059
Grant List119321-1 / / Canadian Institutes of Health Research / Canada
65291-1 / / Canadian Institutes of Health Research / Canada
/ / Canadian Institutes of Health Research / Canada
74433-2 / / Canadian Institutes of Health Research / Canada
74433-1 / / Canadian Institutes of Health Research / Canada

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