Oxysterol-Binding Protein-1 (OSBP1) Modulates Processing and Trafficking of the Amyloid Precursor Protein

BACKGROUND Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes. RESULTS We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol. CONCLUSION These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.National Institute on Aging (AG/NS17485

Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807

The involvement of lipid rafts in the regulation of beta-secretase activity

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Exploring the perception of additional information content in 360° 3D VR video for teaching and learning

360° 3D virtual reality (VR) video is used in education to bring immersive environments into a teaching space for learners to experience in a safe and controlled way. Within 360° 3D VR video, informational elements such as additional text, labelling and directions can be easily incorporated to augment such content. Despite this, the usefulness of this information for learners has not yet been determined. This article presents a study which aims to explore the usefulness of labelling and text within 360° stereoscopic 3D VR video content and how this contributes to the user experience. Postgraduate students from a university in the UK (n = 30) were invited to take part in the study to evaluate VR video content augmented with labels and summary text or neither of these elements. Interconnected themes associated with the user experience were identified from semi-structured interviews. From this, it was established that the incorporation of informational elements resulted in the expansion of the field of view experienced by participants. This “augmented signposting” may facilitate a greater spatial awareness of the virtual environment. Four recommendations for educators developing 360° stereoscopic 3D VR video content are presented

The Personal WebA Research Agenda /

XIV, 221 p. 97 illus.online resource

Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein

Background Evidence from biochemical, epidemiological and genetic findings indicates that cholesterol levels are linked to amyloid-β (Aβ) production and Alzheimer's disease (AD). Oxysterols, which are cholesterol-derived ligands of the liver X receptors (LXRs) and oxysterol binding proteins, strongly regulate the processing of amyloid precursor protein (APP). Although LXRs have been studied extensively, little is known about the biology of oxysterol binding proteins. Oxysterol-binding protein 1 (OSBP1) is a member of a family of sterol-binding proteins with roles in lipid metabolism, regulation of secretory vesicle generation and signal transduction, and it is thought that these proteins may act as sterol sensors to control a variety of sterol-dependent cellular processes. Results We investigated whether OSBP1 was involved in regulating APP processing and found that overexpression of OSBP1 downregulated the amyloidogenic processing of APP, while OSBP1 knockdown had the opposite effect. In addition, we found that OSBP1 altered the trafficking of APP-Notch2 dimers by causing their accumulation in the Golgi, an effect that could be reversed by treating cells with OSBP1 ligand, 25-hydroxycholesterol. Conclusion These results suggest that OSBP1 could play a role in linking cholesterol metabolism with intracellular APP trafficking and Aβ production, and more importantly indicate that OSBP1 could provide an alternative target for Aβ-directed therapeutic.</p

Identification of a novel asthma susceptibility gene on chromosome 1qter and its functional evaluation

Asthma is a multifactorial disease, in which the intricate interplay between genetic and environmental factors underlies the overall phenotype of the disease. Using a genome-wide scan for linkage in a population comprising of Danish families, we identified a novel linked locus on chromosome 1qter (LOD 3.6, asthma) and supporting evidence for this locus was identified for both asthma and atopic-asthma phenotypes in the GAIN (Genetics of Asthma International Network) families. The putative susceptibility gene was progressively localized to a 4.5 Mb region on chromosome 1q adjacent to the telomere, through a series of genotyping screens. Further screening using the pedigree-based association test (PBAT) identified polymorphisms in the OPN3 and CHML genes as being associated with asthma and atopic asthma after correcting for multiple comparisons. We observed that polymorphisms flanking the OPN3 and CHML genes wholly accounted for the original linkage in the Danish population and the genetic association was also confirmed in two separate studies involving the GAIN families. OPN3 and CHML are unique genes with no known function that are related to the pathophysiology of asthma. Significantly, analysis of gene expression at both RNA and protein levels, clearly demonstrated OPN3 expression in lung bronchial epithelia as well as immune cells, while CHML expression appeared minimal. Moreover, OPN3 down-regulation by siRNA knock-down in Jurkat cells suggested a possible role for OPN3 in modulation of T-cell responses. Collectively, these data suggest that OPN3 is an asthma susceptibility gene on 1qter, which unexpectedly may play a role in immune modulation

, H4 cells stably overexpressing APP (H4-APP) were transfected with OSBP1 cDNA as described in Methods

Cell lysates from untransfected cells and those transiently overexpressing OSBP1 were immunoblotted with antibodies to the C-terminus of APP (upper panel), c-myc (middle panel), which detects the myc-tagged OSBP1, and actin, used for loading control. , OSBP1 overexpression decreased PMA-regulated sAPPα secreted levels. Cells were treated with PMA as described in Methods. Proteins from cell lysates and media were separated by SDS-PAGE and lysates were immunoblotted with anti-myc antibody (upper panel). Media samples were analyzed for sAPPα using the 6E10 antibody (middle panel). Cell lysates were also analyzed for CTFα using an antibody to the C-terminus of APP (lower panel). Densitometric analysis of Western blots is shown on the right. *p < 0.05 and **p < 0.01 by Student's test.<p><b>Copyright information:</b></p><p>Taken from "Oxysterol-binding protein-1 (OSBP1) modulates processing and trafficking of the amyloid precursor protein"</p><p>http://www.molecularneurodegeneration.com/content/3/1/5</p><p>Molecular Neurodegeneration 2008;3():5-5.</p><p>Published online 18 Mar 2008</p><p>PMCID:PMC2323375.</p><p></p