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We have recently reported significantly reduced levels of the mRNA of genes critical for the cholesterol biosynthesis pathway in the brains of mice and patients with Huntington's disease (HD), which are indicative of a biological dysfunction. We here show that the brains of R6/2 transgenic mice have progressively decreasing levels of the cholesterol(More)
Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in(More)
OBJECTIVES Cholesterol has been linked to Alzheimer's disease (AD) and plasma 24S-hydroxycholesterol (24OHC) has been suggested as a surrogate marker for brain cholesterol metabolism. This study investigates the relation of 24OHC as well as markers of extracerebral cholesterol homeostasis (lanosterol, lathosterol, cholesterol, LDL-C, HDL-C and(More)
Our recent analyses of the cholesterol biosynthetic pathway in Huntington's disease (HD) cells, in the R6/2 huntingtin-fragment mouse model of HD as well as in human tissues have provided the first evidence of altered activity of this pathway in genetically identifiable HD samples. Here we report that these changes also occur in the full-length-huntingtin(More)
In the central nervous system cholesterol is involved in membrane structure and function. Since the blood-brain barrier efficiently prevents cholesterol uptake from the circulation, de novo synthesis is responsible for almost all cholesterol present there. In mature brain neurons down regulate their cholesterol synthesis and rely on delivery from ApoE(More)
In contrast to their parent molecule cholesterol, two of its side-chain oxidized metabolites are able to cross the blood-brain barrier. There is a concentration-driven flux of 24S-hydroxycholesterol (24S-OHC) from the brain into the circulation, which is of major importance for elimination of excess cholesterol from the brain. The opposite flux of(More)
A number of sentinels sense incoming herpes simplex virus (HSV) virions and initiate an immediate innate response. The first line of defense at the cell surface is TLR2 (Toll-like receptor 2), whose signature signaling activity leads to activation of the key transcription factor NF-κB. We report that the HSV pathogen-associated molecular patterns for TLR2(More)
Mitochondrial disorders are highly heterogeneous conditions characterized by defects of the mitochondrial respiratory chain. Pharmacological activation of mitochondrial biogenesis has been proposed as an effective means to correct the biochemical defects and ameliorate the clinical phenotype in these severely disabling, often fatal, disorders. Pathways(More)
  • Valerio Leoni
  • 2009
Cholesterol plays a crucial structural role in the brain and local synthesis covers almost all the requirements of the brain. To maintain homeostasis, the excess of cholesterol is converted into the more hydrophilic oxysterol 24S-hydroxycholesterol by the neuron-specific enzyme CYP46A1. About 99% of the total excretion of this oxysterol by the brain occurs(More)
Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol(More)