Search results for "membrane proteins"
showing 10 items of 713 documents
Effect of a dominant-negative form of ADAM10 in a mouse model of Alzheimer's disease.
2009
The alpha-secretase cleaves in the non-amyloidogenic pathway the amyloid-beta protein precursor (AbetaPP) within the region of the amyloid-beta peptides to prevent their formation and aggregation in the brain. Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant alpha-secretases. We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AbetaPP (ADAM10 x APP[V717I]) alleviated functional deficits related to Alzheimer's disease. To further demonstrate that this is due to the specific activity of alpha-secretase, we characterized mice overexpressing an inactive form of ADAM10 (ADAM10[E384A]; ADAM10-dn). T…
Down-regulation of Endogenous Amyloid Precursor Protein Processing due to Cellular Aging
2005
Processing of amyloid precursor protein (APP) is a well acknowledged central pathogenic mechanism in Alzheimer disease. However, influences of age-associated cellular alterations on the biochemistry of APP processing have not been studied in molecular detail so far. Here, we report that processing of endogenous APP is down-regulated during the aging of normal human fibroblasts (IMR-90). The generation of intracellular APP cleavage products C99, C83, and AICD gradually declines with increasing life span and is accompanied by a reduced secretion of soluble APP (sAPP) and sAPPalpha. Further, the maturation of APP was reduced in senescent cells, which has been shown to be directly mediated by a…
Alpha-secretase as a therapeutic target.
2007
In the non-amyloidogenic pathway the alpha-secretase cleaves the amyloid precursor protein (APP) within the sequence of Abeta-peptides and precludes their formation. In addition, alpha-secretase cleavage releases an N-terminal extracellular domain with neurotrophic and neuroprotective properties. The disintegrin metalloproteinase ADAM10 has been shown to act as alpha-secretase in vivo, to prevent amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. An increase in alpha-secretase activity therefore is an attractive strategy for treatment of AD and may be achieved by modulating selective signalling pathways. Functional characterization of the human ADAM10 prom…
TCTN3 Mutations Cause Mohr-Majewski Syndrome
2012
Orofaciodigital syndromes (OFDSs) consist of a group of heterogeneous disorders characterized by abnormalities in the oral cavity, face, and digits and associated phenotypic abnormalities that lead to the delineation of 13 OFDS subtypes. Here, by a combined approach of homozygozity mapping and exome ciliary sequencing, we identified truncating TCTN3 mutations as the cause of an extreme form of OFD associated with bone dysplasia, tibial defect, cystic kidneys, and brain anomalies (OFD IV, Mohr-Majewski syndrome). Analysis of 184 individuals with various ciliopathies (OFD, Meckel, Joubert, and short rib polydactyly syndromes) led us to identify four additional truncating TCTN3 mutations in un…
Red Cell Membrane Protein Lateral Mobility in Diabetes Mellitus
1992
In a group of 24 diabetics subdivided for type, we evaluated the red cell membrane protein lateral mobility marking intact red cells with pyrene-3-maleimide (3-PM) and calculating the dimer to monomer fluorescence intensity ratio (Iex/Im). The same fluorescent parameter was determined in a group of 13 normal controls. From the obtained data, it is evident that the red cell membrane protein lateral mobility clearly discriminates normals from diabetics of type 1 and 2. In normals and in diabetics of type 1 and 2 no relationship is present between this fluorescent determinant and the glycometabolic parameters (FBGL and HbA1c); considering all the diabetics, a negative relationship is evident b…
Expression of host defense scavenger receptors in spondylarthropathy
2001
Objective Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram-negative bacteria. HLA–B27 could play a role in this process, but does not account for the many HLA–B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram-negative bacteria: SR class A type I (SR-AI), SR-AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA). Methods Periphera…
GARP inhibits allergic airway inflammation in a humanized mouse model
2016
Background Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. Methods To analyze the therapeutic effects of sGARP, adult NOD/Scidγc−/− (NSG) mice received peripheral blood mononuclear cells (PBMC) …
The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity.
2007
Epithelial to mesenchymal transition (EMT) is implicated in the progression of primary tumours towards metastasis and is likely caused by a pathological activation of transcription factors regulating EMT in embryonic development. To analyse EMT-causing pathways in tumouri-genesis, we identified transcriptional targets of the E-cadherin repressor ZEB1 in invasive human cancer cells. We show that ZEB1 repressed multiple key determinants of epithelial differentiation and cell–cell adhesion, including the cell polarity genes Crumbs3, HUGL2 and Pals1-associated tight junction protein. ZEB1 associated with their endogenous promoters in vivo, and strongly repressed promotor activities in reporter …
Induction of heme oxygenase-1 and adaptive protection against the induction of DNA damage after hyperbaric oxygen treatment.
2000
Hyperbaric oxygen (HBO) treatment of human subjects (i.e. exposure to 100% oxygen at a pressure of 2.5 ATA for a total period of 3 x 20 min) caused clear and reproducible DNA damage in lymphocytes, as detected with the comet assay (single cell gel electrophoresis). Induction of DNA damage was found only after the first HBO exposure and not after further treatments of the same individuals. Furthermore, blood taken 24 h after HBO treatment was significantly protected against the induction of DNA damage by hydrogen peroxide (H(2)O(2)) in vitro, indicating that adaptation occurred due to induction of antioxidant defenses. The cells were not significantly protected against the genotoxic effects …
Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver
2017
Abstract Background and Aims Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. Methods We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at‐risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population‐based Dallas Heart Study (DHS). Re…