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

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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.

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Acknowledgments

This study was supported by the Canadian Institute of Health Research (VL, JP), the Natural Sciences and Engineering Research Council of Canada (JP), the JL Levesque foundation (JP), the Canadian Stroke Network (VL), and the Leducq Fondation (RD).

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Authors and Affiliations

  1. Centre for Studies on Prevention of Alzheimer’s Disease (StoP-AD Centre), Douglas Mental Health University Institute, 6875 Lasalle, Verdun, Quebec, H4H 1R3, Canada

    Valerie Leduc, Louise Théroux, Doris Dea & Judes Poirier

  2. Centre for Studies in the Prevention of Alzheimer’s Disease, McGill University, Montréal, Quebec, Canada

    Judes Poirier

  3. Institut de Recherches Cliniques de Montréal, Department of Nutrition, Université de Montréal, Montréal, Quebec, Canada

    Valerie Leduc & Robert Dufour

Authors
  1. Valerie Leduc
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  2. Louise Théroux
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  5. Judes Poirier
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Correspondence to Judes Poirier.

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Leduc, V., Théroux, L., Dea, D. et al. Effects of rs3846662 Variants on HMGCR mRNA and Protein Levels and on Markers of Alzheimer’s Disease Pathology. J Mol Neurosci 58, 109–119 (2016). https://doi.org/10.1007/s12031-015-0666-7

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