Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer’s disease early phenotypes

Molecular Neurodegeneration

Marie-Claude Potier⁵  Charles Duyckaerts⁵  Jean-Noël Octave²  Nathalie Cartier⁴  Gopal Thinakaran³  Frédéric Saudou⁶  Caroline Benstaali⁶  Fabian Corlier⁵  Mickael Le⁵  Koen Bossers¹  Nathalie Pierrot²  Camille Lemercier-Neuillet⁵  Linda Hanbouch⁵  Luce Dauphinot⁵  Jeanne Laine⁵  Catherine Marquer⁵ 

[1] Neuroregeneration Group, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam 1105 BA, The Netherlands;Université catholique de Louvain, Institute of Neuroscience, Brussels 1200, Belgium;Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA;INSERM U986 94276 Le Kremlin-Bicêtre, and University Paris-Sud, 91400 Orsay, France;Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, UM 75, U 1127, UMR 7225, ICM, 75013 Paris, France;Institut Curie, CNRS UMR, Orsay 91405, France

关键词: Axonal transport;    Neurons;    Endosomes;    Cholesterol;    Amyloid precursor protein;    Alzheimer’s disease;   

Others  :  1138550
DOI  :  10.1186/1750-1326-9-60

 received in 2014-03-11, accepted in 2014-12-03,  发布年份 2014

【 摘 要 】

Background

It is suspected that excess of brain cholesterol plays a role in Alzheimer’s disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes.

Results

We thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live-imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-β42 secretion.

Conclusions

Membrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets.

【 授权许可】

   
2014 Marquer et al.; licensee BioMed Central.

【 图 表 】

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