Biomedical subjects

Cornelia Franke

Publications and source records attributed to Cornelia Franke.

4 recordsLinked to original sources

PubMed2007

Cholesterol: Coupling between membrane microenvironment and ABC transporter activity.

Lipid composition of biological membranes is closely related to the function of the ATP-binding cassette (ABC) transporter P-Glycoprotein (Pgp). Herein, we studied how membrane physico-chemical properties affect Pgp-activity. We effectively modulated the cellular cholesterol content using methyl-beta-cyclodextrin (MbetaCD) and MbetaCD-cholesterol-inclusion complex. Pgp was not liberated from the plasma membrane during cholesterol modulation and functional inhibition of Pgp was related to varying cholesterol levels in the plasma membrane. Our data indicate that membrane fluidity does not solely account for cholesterol dependent modifications of Pgp-activity. Therefore, we isolated lipid rafts and examined distinct membrane microdomains. Both depletion and cholesterol enrichment induces a disassembly of lipid rafts. In cholesterol-depleted cell membranes a shift in the Pgp localisation to detergent soluble fractions was observed. Enrichment of membrane cholesterol changed lipid raft distribution but not the localisation of Pgp. From our data we conclude that Pgp-transport capacity depends on accurate lipid raft properties.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment.

The present study determined if chronic simvastatin administration in vivo would provide neuroprotection in brain cells isolated from guinea pigs after challenge with the Bcl-2 inhibitor HA 14-1 or the NO donor sodium nitroprusside (SNP). Bcl-2 levels were significantly increased in brains of simvastatin-treated guinea pigs while levels of the pro-apoptotic protein Bax were significantly reduced. The ratio of Bax/Bcl-2, being a critical factor of the apoptotic state of cells, was significantly reduced in simvastatin-treated animals. Cholesterol levels in the brain remained unchanged in the simvastatin group. Brain cells isolated from simvastatin-treated guinea pigs were significantly less vulnerable to mitochondrial dysfunction and caspase-activation. These results provide new insight into potential mechanisms for the protective actions of statins within the CNS where programmed cell death has been implicated.

Animals↗

PubMed2006

Heterologously expressed GLT-1 associates in approximately 200-nm protein-lipid islands.

The glutamate transporter GLT-1 from Rattus norvegicus was expressed at high level in baby hamster kidney (BHK-21) cells by the Semliki Forest Virus expression system. We examined the expressed GLT-1 in the plasma membrane and found that the transporter accumulates in detergent-insoluble lipid-protein assemblies. Freeze-fracture, immunogold labeling, and electron microscopy revealed that GLT-1 forms approximately 200-nm protein-rich islands in the plasma membrane. Cholesterol depletion in living cells resulted in a dispersion of the GLT-1 islands, indicating that they are the result of lipid-protein rather than protein-protein interactions. Disruption of GLT-1 islands and dispersion of GLT-1 goes along with a reduction of the glutamate transport activity. Our direct visualization of lipid-protein islands in the plasma membrane of tissue culture cells suggests that the reported clustering of glutamate transporters and their cholesterol-dependent transport activity in cells is likewise connected to their association with cholesterol-rich microdomains in the plasma membrane.

Animals↗

PubMed2004

Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex.

Statins have been reported to lower the risk of developing Alzheimer's disease; however, the mechanism of this potentially important neuroprotective action is not understood. Lowering cholesterol levels does not appear to be the primary mechanism. Statins have pleiotropic effects in addition to lowering cholesterol, and statins may act on several different pathways involving distinct gene expression patterns that would be difficult to determine by focusing on a few genes or their products in a single study. In addition, gene expression patterns may be specific to a particular statin. To understand the molecular targets of statins in brain, DNA microarrays were used to identify gene expression patterns in the cerebral cortex of mice chronically treated with lovastatin, pravastatin, and simvastatin. Furthermore, brain statin levels were determined using liquid chromatography/tandem mass spectrometry. These studies revealed 15 genes involved in cell growth and signaling and trafficking that were similarly changed by all three statins. Overall, simvastatin had the greatest influence on expression as demonstrated by its ability to modify the expression of 23 genes in addition to those changed by all three drugs. Of particular interest was the expression of genes associated with apoptotic pathways that were altered by simvastatin. Reverse transcription-polymerase chain reaction experiments confirmed the microarray findings. All three drugs were detected in the cerebral cortex, and acute experiments revealed that statins are relatively rapidly removed from the brain. These results provide new insight into possible mechanisms for the potential efficacy of statins in reducing the risk of Alzheimer's disease and lay the foundation for future studies.

Animals↗