About 20% increase in the subsequent risk of asthma was both found in children delivered by elective and emergency CS. The increasing rates of CS worldwide might partly explain the concomitant rise in asthma during the same time period.
Degeneration of neurons in Alzheimer's disease is mediated by -amyloid peptide by diverse mechanisms, which include a putative apoptotic component stimulated by unidentified signaling events. This report describes a novel -amyloid peptide-binding protein (denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved structure. The BBP subtype bound human -amyloid peptide in vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to -amyloid peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to -amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic -amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease.Genetic and biochemical data have coalesced to establish that -amyloid peptide (A) 1 is a causative factor in neuron death and the consequent dimunition of cognitive abilities observed in Alzheimer's disease (1, 2). Plasma lipoproteins and their cell surface receptors influence sequestration and clearance of soluble A, contributing to the etiology of the disease (3-6). Inflammatory responses and oxidative damage also appear to contribute to the loss of neurons in Alzheimer's disease (7-10). Although the earliest cellular perturbations remain unclear, recent findings indicate that A may act as an initiating factor in the death of neurons by inducing signaling pathways leading to apoptosis (11-17). However, the specific molecular target(s) transducing these A effects has not been identified. The intracellular protein ERAB can bind A in vitro, and neuroblastoma cells expressing recombinant ERAB undergo apoptosis when treated with exogenously added A (18), but the mechanism by which ERAB may affect apoptotic signaling remains obscure. We identified a novel human -amyloid peptide binding protein (BBP) utilizing yeast 2-hybrid technology. Analysis of the BBP amino acid sequence revealed the presence of a structural module related to that of the 7 transmembrane domain G protein-coupled receptor superfamily and known to be important in heterotrimeric G protein activation. Data suggest that BBP mediates cellular vulnerability to A toxicity through a G protein-regulated program of cell death. Two related proteins (BLP1, BLP2; BBP-like proteins) were identified by sequence and structural similarities to BBP, but only the BBP subtype regulates a response to A.
EXPERIMENTAL PROCEDURESYeast Two-hybrid Systems-Yeast 2-hybrid (Y2H) expression plasmids were constructed in the vectors pAS2 and pACT2 (19). Strain CY770 (20) served as host for Y2H assays. Sequences encoding A 42 were amplified by PCR using primers incorporating restriction sites for subsequent ligation into pAS2, using a human APP (amyloid precursor protein) cDNA clone as template. A Y2H plasmid library consisting of cDNA fragments isolated from human fetal brain clone...
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