Neuronal Cholesterol Accumulation Induced by Cyp46a1 Down-Regulation in Mouse Hippocampus Disrupts Brain Lipid Homeostasis

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

Recherche d'antifongiques inhibiteurs de l'adhésion : synthèse et activité biologique de thio-derivés lipophiles (thiocyanates, thiourées, azoles mono et polycycliques)

Non disponible / Not availabl

Toxicologie des phatlates et grossesse (implication de PPARg, conséquences sur le lipidome de cellules placentaires)

PARIS-BIUP (751062107) / SudocSudocFranceF

Mise au point et validation d'une méthode de contrôle analytique d'un sirop antitussif

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude du rôle du bêta-amyloïde dans la maladie d'Alzheimer (stress oxydant et implication des lipides)

PARIS-BIUP (751062107) / SudocSudocFranceF

Electrochemical removal of the picolinoyl group under mild acidic conditions. Application to the protection of amines in peptide synthesis

International audienc

First N-alkyl heterolysis of tertiary benzamides in neutral conditions

International audienc

Influence of steric crowding on the electrochemical reduction of substituted tertiary pyridylcarboxamides in aqueous acidic medium

International audienc

ChemInform Abstract: First N-Alkyl Heterolysis of Tertiary Benzamides in Neutral Conditions.

International audienc

Molecular Network-Based Identification of Tramadol Metabolites in a Fatal Tramadol Poisoning

International audienceIdentification of xenobiotics and their phase I/II metabolites in poisoned patients remains challenging. Systematic approaches using bioinformatic tools are needed to detect all compounds as exhaustively as possible. Here, we aimed to assess an analytical workflow using liquid chromatography coupled to high-resolution mass spectrometry with data processing based on a molecular network to identify tramadol metabolites in urine and plasma in poisoned patients. The generated molecular network from liquid chromatography coupled to high-resolution tandem mass spectrometry data acquired in both positive and negative ion modes allowed for the identification of 25 tramadol metabolites in urine and plasma, including four methylated metabolites that have not been previously reported in humans or in vitro models. While positive ion mode is reliable for generating a network of tramadol metabolites displaying a dimethylamino radical in their structure, negative ion mode was useful to cluster phase II metabolites. In conclusion, the combined use of molecular networks in positive and negative ion modes is a suitable and robust tool to identify a broad range of metabolites in poisoned patients, as shown in a fatal tramadol-poisoned patient