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Hum Mol Genet. 2015 Nov 1;24(21):5965-76. doi: 10.1093/hmg/ddv268. Epub 2015 Sep 10.

Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology.

Author information

1
INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France, Université Paris Descartes, Paris 75006, France.
2
INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France.
3
Division of Cellular Neurobiology, Zoological Institute, University of Braunschweig, Braunschweig 38106, Germany, AG NIND, HZI, Inhoffenstraße 7, Braunschweig D-38124, Germany.
4
Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS894, Paris 75014, France.
5
Chimie-Toxicologie Analytique et Cellulaire, EA 4463 and.
6
EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris 75006, France.
7
ICM, Hopital Pitie-Salpetriere, CNRS UMR7225, INSERM UMRS975, UPMC, Paris 75013, France.
8
Université de Lille, UDSL, Lille 59045, France, INSERM UMR1172, Jean-Pierre Aubert Research Centre, Lille 59045, France and.
9
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.
10
INSERM U1169/MIRCen CEA, Fontenay aux Roses 92265, France, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France, nathalie.cartier@inserm.fr.

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.

PMID:
26358780
DOI:
10.1093/hmg/ddv268
[Indexed for MEDLINE]

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