title: Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology.
abstract: Alzheimer's disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. In AD patients, the concentration of 24S-hydroxycholesterol in the plasma and the cerebrospinal fluid are lower than in healthy controls. The THY-Tau22 mouse is a model of AD-like Tau pathology without amyloid pathology. We used this model to investigate the potential association between Tau pathology and CYP46A1 modulation. The amounts of CYP46A1 and 24S-hydroxycholesterol in the hippocampus were lower in THY-Tau22 than control mice. We used an adeno-associated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on THY-Tau22 mouse phenotype. Injection of the AAV-CYP46A1 vector into the hippocampus of THY-Tau22 mice led to CYP46A1 and 24S-hydroxycholesterol content normalization. The cognitive deficits, impaired long-term depression and spine defects that characterize the THY-Tau22 model were completely rescued, whereas Tau hyperphosphorylation and associated gliosis were unaffected. These results argue for a causal link between CYP46A1 protein content and memory impairments that result from Tau pathology. Therefore, CYP46A1 may be a relevant therapeutic target for Tauopathies and especially for AD.
authors.affiliation: INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France, Université Paris Descartes, Paris 75006, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Burlot
authors.affiliation: INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Braudeau
authors.affiliation: Division of Cellular Neurobiology, Zoological Institute, University of Braunschweig, Braunschweig 38106, Germany, AG NIND, HZI, Inhoffenstraße 7, Braunschweig D-38124, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Michaelsen-Preusse
authors.affiliation: Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS894, Paris 75014, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Potier
authors.affiliation: Chimie-Toxicologie Analytique et Cellulaire, EA 4463 and.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ayciriex
authors.affiliation: EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris 75006, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Varin
authors.affiliation: INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Gautier
authors.affiliation: INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France, Université Paris Descartes, Paris 75006, France.
authors.forename: Fathia
authors.initials: F
authors.lastname: Djelti
authors.affiliation: INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France, Université Paris Descartes, Paris 75006, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Audrain
authors.affiliation: ICM, Hopital Pitie-Salpetriere, CNRS UMR7225, INSERM UMRS975, UPMC, Paris 75013, France.
authors.forename: Luce
authors.initials: L
authors.lastname: Dauphinot
authors.affiliation: Université de Lille, UDSL, Lille 59045, France, INSERM UMR1172, Jean-Pierre Aubert Research Centre, Lille 59045, France and.
authors.forename: Francisco-Jose
authors.initials: FJ
authors.lastname: Fernandez-Gomez
authors.affiliation: Université de Lille, UDSL, Lille 59045, France, INSERM UMR1172, Jean-Pierre Aubert Research Centre, Lille 59045, France and.
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Caillierez
authors.affiliation: Chimie-Toxicologie Analytique et Cellulaire, EA 4463 and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Laprévote
authors.affiliation: EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris 75006, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Chimie-Toxicologie Analytique et Cellulaire, EA 4463 and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Auzeil
authors.affiliation: ICM, Hopital Pitie-Salpetriere, CNRS UMR7225, INSERM UMRS975, UPMC, Paris 75013, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Potier
authors.affiliation: Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS894, Paris 75014, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Dutar
authors.affiliation: Division of Cellular Neurobiology, Zoological Institute, University of Braunschweig, Braunschweig 38106, Germany, AG NIND, HZI, Inhoffenstraße 7, Braunschweig D-38124, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Korte
authors.affiliation: Université de Lille, UDSL, Lille 59045, France, INSERM UMR1172, Jean-Pierre Aubert Research Centre, Lille 59045, France and CHRU-Lille, Faculté de Médecine, Lille 59037, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Université de Lille, UDSL, Lille 59045, France, INSERM UMR1172, Jean-Pierre Aubert Research Centre, Lille 59045, France and CHRU-Lille, Faculté de Médecine, Lille 59037, France.
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.affiliation: INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France, nathalie.cartier@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cartier
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000818:Animals; D000072556:Cholesterol 24-Hydroxylase; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D008569:Memory Disorders / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins
chemical_list: D006888:Hydroxycholesterols; D016875:tau Proteins; C044563:24-hydroxycholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase