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

TY - JOUR

T1 - Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer's disease early phenotypes

AU - Marquer, Catherine

AU - Laine, Jeanne

AU - Dauphinot, Luce

AU - Hanbouch, Linda

AU - Lemercier-Neuillet, Camille

AU - Pierrot, Nathalie

AU - Bossers, K.

AU - Le, Mickael

AU - Corlier, Fabian

AU - Benstaali, Caroline

AU - Saudou, Frédéric

AU - Thinakaran, Gopal

AU - Cartier, Nathalie

AU - Octave, Jean-Noël

AU - Duyckaerts, Charles

AU - Potier, Marie-Claude

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Alzheimer Disease

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Cell Membrane

KW - Cholesterol

KW - Disease Models, Animal

KW - Memory

KW - Neurons

KW - Phenotype

KW - Rats, Sprague-Dawley

KW - Transcriptome

U2 - 10.1186/1750-1326-9-60

DO - 10.1186/1750-1326-9-60

M3 - Article

C2 - 25524049

SN - 1750-1326

VL - 9

SP - 60

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

ER -