The formation of giant plasma membrane vesicles enable new insights into the regulation of cholesterol efflux.

The formation of giant plasma membrane vesicles enable new insights into the regulation of cholesterol efflux. Exp Cell Res. 2018 Mar 06;: Authors: Sedgwick A, Olivia Balmert M, D'Souza-Schorey C Abstract Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4. Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation. Conversely, pharmacological inhibition of cholesterol efflux blocks GPMV formation. We show that microtubule stabilization via paclitaxel treatment and increased tubulin acetylation via HDAC6 inhibition promotes the formation of GPMVs with concomitant reduction in cellular cholesterol in a cell model of NPC disease. The pan-deacetylase inhibitor panobinostat, which has been shown to reduce the severity of cholesterol storage in NPC, elicited a similar response. Further, the disruption of actin polymerization inhibits the formation of GPMVs, whereas the small GTP-binding protein Arl4c promotes actin remodeling at sites overlapping with GPMV formation. Thus, monitoring...
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research

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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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Source: Fight Aging! - Category: Research Authors: Tags: Healthy Life Extension Community Source Type: blogs
T, Colell A Abstract Macroautophagy/autophagy failure with the accumulation of autophagosomes is an early neuropathological feature of Alzheimer disease (AD) that directly affects amyloid beta (Aβ) metabolism. Although loss of presenilin 1 function has been reported to impair lysosomal function and prevent autophagy flux, the detailed mechanism leading to autophagy dysfunction in AD remains to be elucidated. The resemblance between pathological hallmarks of AD and Niemann-Pick Type C disease, including endosome-lysosome abnormalities and impaired autophagy, suggests cholesterol accumulation as a common link. ...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
Abstract Increasing evidence implicates lysosomal dysfunction in the pathogenesis of neurodegenerative diseases, including the rare inherited lysosomal storage disorders (LSDs) and the most common neurodegenerative diseases, such as Alzheimer's and Parkinson's disease (AD and PD). While the triggers of the lysosomal impairment may involve the accumulated macromolecules or dysfunction of the lysosomal enzymes, the role of the lysosomal glycocalyx in the lysosomal (dys)function has not been studied. The goal of this work was to analyze whether there are changes in the lysosomal glycocalyx in a cellular model of a LS...
Source: Molecular and Cellular Proteomics : MCP - Category: Molecular Biology Authors: Tags: Mol Cell Proteomics Source Type: research
Hydroxypropyl-β-cyclodextrin formulated in nasal chitosan microspheres as candidate therapeutic agent in Alzheimer's disease. Curr Drug Deliv. 2017 Oct 19;: Authors: Rassu G, Gavini E, Carta A, Obinu A, Porcu EP, Giunchedi P Abstract Hydroxypropyl-β-cyclodextrin (HP-CD) is a hydroxyalkyl derivative of native β-cyclodextrin, cyclic oligosaccharide able to form inclusion complexes with many drugs and biomolecules [1]. Cyclodextrins have a possible neuroprotective effect due to their capability to extract and deplete cholesterol from cell membranes [1]. HP-CD is classified as an excipient ...
Source: Current Drug Delivery - Category: Drugs & Pharmacology Authors: Tags: Curr Drug Deliv Source Type: research
Publication date: Available online 6 September 2017 Source:Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids Author(s): Martina Korber, Isabella Klein, Günther Daum Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set ...
Source: Biochimica et Biophysica Acta (BBA) Molecular and Cell Biology of Lipids - Category: Lipidology Source Type: research
Abstract Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester stor...
Source: Biochimica et Biophysica Acta - Category: Biochemistry Authors: Tags: Biochim Biophys Acta Source Type: research
Publication date: Available online 31 January 2017 Source:Molecular Aspects of Medicine Author(s): Andrea Leiva, Enrique Guzmán-Gutiérrez, Susana Contreras-Duarte, Bárbara Fuenzalida, Claudette Cantin, Lorena Carvajal, Rocío Salsoso, Jaime Gutiérrez, Fabián Pardo, Luis Sobrevia Adenosine as well as agonists and antagonists for the four adenosine receptor subtypes (A1R, A2AR, A2BR and A3R) play a role in several key physiological and pathophysiological processes, including the regulation of vascular tone, thrombosis, immune response, inflammation, and angiogenesis. This review focu...
Source: Molecular Aspects of Medicine - Category: Molecular Biology Source Type: research
by Stjepko Cermak, Marko Kosicek, Aleksandra Mladenovic-Djordjevic, Kosara Smiljanic, Selma Kanazir, Silva Hecimovic Proper function of lysosomes is particularly important in neurons, as they cannot dilute accumulated toxic molecules and aggregates by cell division. Thus, impairment of lysosomal function plays an important role in neuronal degeneration and in the pathogenesis of numerous neurodegenerative diseas es. In this work we analyzed how inhibition and/or loss of the major lysosomal proteases, the cysteine cathepsins B and L (CtsB/L), affects lysosomal function, cholesterol metabolism and degradation of the key Alz...
Source: PLoS One - Category: Biomedical Science Authors: Source Type: research
This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum.
Source: Biochimica et Biophysica Acta (BBA) Molecular and Cell Biology of Lipids - Category: Lipidology Source Type: research
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