title: CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer's disease.
abstract: Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.
authors.affiliation: 1 INSERM U1169 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Djelti
authors.affiliation: 1 INSERM U1169 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Braudeau
authors.affiliation: 1 INSERM U1169 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Eloise
authors.initials: E
authors.lastname: Hudry
authors.affiliation: 2 CNRS URA2210 MIRCen CEA Fontenay aux Roses 92265, and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Dhenain
authors.affiliation: 3 EA7331, Université Paris Descartes Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Varin
authors.affiliation: 3 EA7331, Université Paris Descartes Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: 4 UMR S1127, and INSERM U1127, and CNRS UMR7225, and ICM, Sorbonne Université, UPMC Univ Paris 06 75013, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Marquer
authors.affiliation: 4 UMR S1127, and INSERM U1127, and CNRS UMR7225, and ICM, Sorbonne Université, UPMC Univ Paris 06 75013, Paris, France.
authors.forename: Farah
authors.initials: F
authors.lastname: Chali
authors.affiliation: 5 Chimie-Toxicologie Analytique et Cellulaire, EA 4463, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ayciriex
authors.affiliation: 5 Chimie-Toxicologie Analytique et Cellulaire, EA 4463, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Auzeil
authors.affiliation: 1 INSERM U1169 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Sandro
authors.initials: S
authors.lastname: Alves
authors.affiliation: 4 UMR S1127, and INSERM U1127, and CNRS UMR7225, and ICM, Sorbonne Université, UPMC Univ Paris 06 75013, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Langui
authors.affiliation: 4 UMR S1127, and INSERM U1127, and CNRS UMR7225, and ICM, Sorbonne Université, UPMC Univ Paris 06 75013, Paris, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Potier
authors.affiliation: 5 Chimie-Toxicologie Analytique et Cellulaire, EA 4463, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Laprevote
authors.affiliation: 3 EA7331, Université Paris Descartes Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, 75006 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Vidaud
authors.affiliation: 4 UMR S1127, and INSERM U1127, and CNRS UMR7225, and ICM, Sorbonne Université, UPMC Univ Paris 06 75013, Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: 4 UMR S1127, and INSERM U1127, and CNRS UMR7225, and ICM, Sorbonne Université, UPMC Univ Paris 06 75013, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Miles
authors.affiliation: 1 INSERM U1169 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aubourg
authors.affiliation: 1 INSERM U1169 Le Kremlin-Bicêtre and Université Paris-Sud, 91400 Orsay, France nathalie.cartier@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D000072556:Cholesterol 24-Hydroxylase; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006706:Homeostasis / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase
keywords: 24S-hydroxycholesterol; Alzheimer’s disease; Cyp46a1; cholesterol; neurodegeneration