We have investigated whether side chainhydroxylated cholesterol species are important for elimination of cholesterol from the brain. Plasma concentrations of 24-hydroxycholesterol (24-OH-Chol) in the internal jugular vein and the brachial artery in healthy volunteers were consistent with a net flux of this steroid from the brain into the circulation, corresponding to elimination of -4 mg cholesterol during a 24-h period in adults. Results of experiments with rats exposed to '802were also consistent with a flux of 24-OH-Chol from the brain into the circulation. No other oxysterol measured showed a similar behavior as 24-OH-Chol. These results and the finding that the concentration of 24-OH-Chol was 30-to 1500-fold higher in the brain than in any other organ except the adrenals indicate that the major part of 24-OH-Chol present in the circulation originates from the brain. Both the 24-OH-Chol present in the brain and in the circulation were the 24S-stereoisomer. In contrast to other oxysterols, levels of plasma 24-OH-Chol were found to be markedly dependent upon age. The ratio between 24-OH-Chol and cholesterol in plasma was -5 times higher during the first decade of life than during the sixth decade. There was a high correlation between levels of 24-OH-Chol in plasma and cerebrospinal fluid. It is suggested that the flux of 24-OHChol from the brain is important for cholesterol homeostasis in this organ. The brain is the most cholesterol-rich organ in the body. However, surprisingly little is known about the mechanism regulating cholesterol homeostasis in this organ. Very little cholesterol is taken up from circulating lipoproteins due to the efficient blood-brain barrier (1). The local synthesis of cholesterol is also very low, and it has been reported that only -0.1% of newly synthesized cholesterol in adult monkeys is present in the brain (2). If this is valid also in adult humans, only 1-2 mg of cholesterol would be synthesized each day. From in vitro experiments on slices of rat brain, it was calculated that the half-life of cholesterol is -6 months (3). However, the very low uptake and synthesis of cholesterol in the brain must be balanced by some mechanism for removal of cholesterol. If very little high-density lipoprotein-dependent cholesterol transport occurs, the possibility should be considered that there is a conversion of cholesterol into metabolites that may pass the blood-brain barrier more easily than cholesterol itself.Recently, we described a new mechanism for elimination of intracellular cholesterol in macrophages, involving conversion of cholesterol into 27-hydroxycholesterol (27-OH-Chol; also denoted (25R)-cholest-5-ene-3/3,26-diol) and 3,B-hydroxy-5-cholestenoic acid (4). These compounds are more polar than cholesterol and easily transported out from the cells (4, 5). We have also shown that there is a continuous flux of 27-OH-Chol and other 27-oxygenated steroids from extrahepatic sources to the liver, where these compounds are rapidly metabolized into bile acids (5).We have previous...

Background Resolution is the final stage of the inflammatory response, when restoration of tissue occurs. Failure may lead to chronic neuroinflammation, known as part of pathology in Alzheimer’s disease (AD) brain. Methods Specialized pro-resolving mediators (SPMs), receptors, biosynthetic enzyme, and downstream effectors involved in resolution were analyzed in post mortem hippocampal tissue from AD-patients and non-AD subjects. SPMs were analyzed in cerebrospinal fluid (CSF). Results Presence of SPMs and SPM receptors was demonstrated in the human brain. Levels of the SPM lipoxin A4 (LXA4) were reduced in AD - both in CSF and hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in AD brains. LXA4 and RvD1 levels in CSF correlated to mini-mental state examination (MMSE) scores. Conclusions The resolution pathway exists in the brain and described alterations strongly suggest its dysfunction in AD. Correlations with MMSE suggest a connection with cognitive function in AD.

We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.