Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Increase in membrane cholesterol of neurons in culture recapitulates AlzheimerM-bM-^@M-^Ys disease early phenotypes.

ABSTRACT: Levels of membrane-associated cholesterol were shown to be increased in the brain of individuals with sporadic AlzheimerM-bM-^@M-^Ys disease (AD) and correlated with the severity of the disease. We previously found that heavy membrane cholesterol burden promotes amyloid precursor protein (APP) endocytosis and processing, leading to increased amyloid-M-oM-^AM-"M-oM-^@M- M-oM-^@M-(AM-oM-^AM-") secretion. We hypothesized that such an increase of cholesterol could trigger sporadic AD. We thus acutely loaded the plasma membrane of neurons in culture with cholesterol to reach the 30 % increase observed in AD brains. We showed by multiplex electro-chemiluminescence immuno-assay that transient membrane cholesterol loading produced a significant increase of AM-oM-^AM-"42 secretion. We also found that early endosomes were enlarged and more prone to aggregation using confocal and electron microscopy and that APP vesicular transport in neuronal processes was slowed down using fluorescence live-imaging. In addition, treatment of neurons with cholesterol induced changes in gene expression profile that are reminiscent of early AD. This model of membrane cholesterol increase in cultured neurons reproduces most of early AD changes and could thus be relevant for deciphering early mechanisms and design new targets for sporadic AD. In this study, we loaded the plasma membrane of neurons with 30% more cholesterol and observed the effects on gene expression. We compared gene expression of primary hippocampal neurons treated or not with cholesterol using 4 independant replicates in each group.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Luce Dauphinot

PROVIDER: E-GEOD-46221 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Marquer Catherine C Laine Jeanne J Dauphinot Luce L Hanbouch Linda L Lemercier-Neuillet Camille C Pierrot Nathalie N Bossers Koen K Le Mickael M Corlier Fabian F Benstaali Caroline C Saudou Frédéric F Thinakaran Gopal G Cartier Nathalie N Octave Jean-Noël JN Duyckaerts Charles C Potier Marie-Claude MC

Molecular neurodegeneration 20141218

<h4>Background</h4>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.<h4>Results</h4>We thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD ...[more]

PMID: 25524049

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Project description:Kyrtsos2011 - A systems biology model for Alzheimer's disease (Cholesterol in AD) Encoded non-curated model. Issues: - Confusing HmgCoA differential equation - Confusing d2 and t1 parameters - Lack of initial values for several key species This model is described in the article: Of Mice and Math: A Systems Biology Model for Alzheimer's disease Kyrtsos, Christina Rose UMD Theses and Dissertations Abstract: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the US, affecting over 1 in 8 people over the age of 65. There are several well-known pathological changes in the brains of AD patients, namely: the presence of diffuse beta amyloid plaques derived from the amyloid precursor protein (APP), hyper-phosphorylated tau protein, neuroinflammation and mitochondrial dysfunction. Recent studies have shown that cholesterol levels in both the plasma and the brain may play a role in disease pathogenesis, however, this exact role is not well understood. Additional proteins of interest have also been identified (ApoE, LRP-1, IL-1) as possible contributors to AD pathogenesis. To help understand these roles better, a systems biology mathematical model was developed. Basic principles from graph theory and control analysis were used to study the effect of altered cholesterol, ApoE, LRP and APP on the system as a whole. Negative feedback regulation and the rate of cholesterol transfer between astrocytes and neurons were identified as key modulators in the level of beta amyloid. Experiments were run concurrently to test whether decreasing plasma and brain cholesterol levels with simvastatin altered the expression levels of beta amyloid, ApoE, and LRP-1, to ascertain the edge directions in the network model and to better understand whether statin treatment served as a viable treatment option for AD patients. The work completed herein represents the first attempt to create a systems-level mathematical model to study AD that looks at intercellular interactions, as well as interactions between metabolic and inflammatory pathways. This model is hosted on BioModels Database and identified by: MODEL1504240000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Increase in membrane cholesterol of neurons in culture recapitulates AlzheimerM-bM-^@M-^Ys disease early phenotypes.

Publications

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

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