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

被引：98

作者：

Burlot, Marie-Anne ^{[1
,2
,3
]}

Braudeau, Jerome ^{[1
,2
]}

Michaelsen-Preusse, Kristin ^{[4
,5
]}

Potier, Brigitte ^{[6
]}

Ayciriex, Sophie ^{[7
]}

Varin, Jennifer ^{[8
]}

Gautier, Benoit ^{[1
,2
]}

Djelti, Fathia ^{[1
,2
,3
]}

Audrain, Mickael ^{[1
,2
,3
]}

Dauphinot, Luce ^{[9
]}

Fernandez-Gomez, Francisco-Jose ^{[10
,11
]}

Caillierez, Raphaelle ^{[10
,11
]}

Laprevote, Olivier ^{[7
]}

Bieche, Ivan ^{[8
]}

Auzeil, Nicolas ^{[7
]}

Potier, Marie-Claude ^{[9
]}

Dutar, Patrick ^{[6
]}

Korte, Martin ^{[4
,5
]}

Buee, Luc ^{[10
,11
,12
]}

Blum, David ^{[10
,11
,12
]}

Cartier, Nathalie ^{[1
,2
]}

机构：

[1] INSERM, U1169, MIRCen, CEA Fontenay Aux Roses, F-92265 Fontenay Aux Roses, France

[2] Univ Paris Saclay, Univ Paris Sud, F-91400 Orsay, France

[3] Univ Paris 05, F-75006 Paris, France

[4] Tech Univ Carolo Wilhelmina Braunschweig, Inst Zool, Div Cellular Neurobiol, D-38106 Braunschweig, Germany

[5] HZI, AG NIND, D-38124 Braunschweig, Germany

[6] Univ Paris 05, INSERM UMRS894, Ctr Psychiat & Neurosci, Sorbonne Paris Cite, F-75014 Paris, France

[7] Univ Paris 05, Chim Toxicol Analyt & Cellulaire, Fac Sci Pharmaceut & Biol, EA 4463,Sorbonne Paris Cite, F-75006 Paris, France

[8] Univ Paris 05, EA7331, Fac Sci Pharmaceut & Biol, Sorbonne Paris Cite, F-75006 Paris, France

[9] UPMC, Hop Pitie Salpetriere, ICM, CNRS UMR7225,INSERM UMRS975, F-75013 Paris, France

[10] Univ Lille, UDSL, F-59045 Lille, France

[11] INSERM UMR1172, Jean Pierre Aubert Res Ctr, F-59045 Lille, France

[12] CHRU Lille, Fac Med, F-59037 Lille, France

来源：

HUMAN MOLECULAR GENETICS | 2015年 / 24卷 / 21期

关键词：

THY-TAU22 MOUSE MODEL; TRANSGENIC MODEL; APOLIPOPROTEIN-E; NEUROFIBRILLARY TANGLES; SYNAPTIC-TRANSMISSION; COGNITIVE-IMPAIRMENT; RECEPTOR ACTIVATION; MASS-SPECTROMETRY; PYRAMIDAL NEURONS; CANDIDATE MARKER;

D O I：

10.1093/hmg/ddv268

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：5965 / 5976

页数：12

共 66 条

[1] 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux [J].