neuronal cholesterol accumulation induced by cyp46a1 down-regulation in mouse hippocampus disrupts brain lipid homeostasis

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ID: 239823
2017
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Abstract
Impairment in cholesterol metabolism is associated with many neurodegenerative disorders including Alzheimer's disease (AD). However, the lipid alterations underlying neurodegeneration and the connection between altered cholesterol levels and AD remains not fully understood. We recently showed that cholesterol accumulation in hippocampal neurons, induced by silencing Cyp46a1 gene expression, leads to neurodegeneration with a progressive neuronal loss associated with AD-like phenotype in wild-type mice. We used a targeted and non-targeted lipidomics approach by liquid chromatography coupled to high-resolution mass spectrometry to further characterize lipid modifications associated to neurodegeneration and cholesterol accumulation induced by CYP46A1 inhibition. Hippocampus lipidome of normal mice was profiled 4 weeks after cholesterol accumulation due to Cyp46a1 gene expression down-regulation at the onset of neurodegeneration. We showed that major membrane lipids, sphingolipids and specific enzymes involved in phosphatidylcholine and sphingolipid metabolism, were rapidly increased in the hippocampus of AAV-shCYP46A1 injected mice. This lipid accumulation was associated with alterations in the lysosomal cargoe, accumulation of phagolysosomes and impairment of endosome-lysosome trafficking. Altogether, we demonstrated that inhibition of cholesterol 24-hydroxylase, key enzyme of cholesterol metabolism leads to a complex dysregulation of lipid homeostasis. Our results contribute to dissect the potential role of lipids in severe neurodegenerative diseases like AD.
Reference Key
ayciriex2017frontiersneuronal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Sophie Ayciriex;Fathia Djelti;Fathia Djelti;Sandro Alves;Sandro Alves;Anne Regazzetti;Mathieu Gaudin;Mathieu Gaudin;Jennifer Varin;Dominique Langui;Ivan Bièche;Eloise Hudry;Delphine Dargère;Patrick Aubourg;Patrick Aubourg;Nicolas Auzeil;Olivier Laprévote;Olivier Laprévote;Nathalie Cartier;Nathalie Cartier
Journal international journal of nanomedicine
Year 2017
DOI
10.3389/fnmol.2017.00211
URL
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00211/full
Keywords
neurodegeneration gene silencing cholesterol lipidomics neuropsychiatry biological psychiatry

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