Anti-APP polyclonal antibody

Extracellular deposition of amyloid-beta (A beta) protein, a fragment of membrane glycoprotein called beta-amyloid precursor transmembrane protein (beta APP), is the major characteristic for the Alzheimer's disease (AD). However, the structural and mechanistic information of forming Ab protein aggregates in a lag phase in cell exterior has been still limited. Here, we have performed multiple all-atom molecular dynamics simulations for physiological 42-residue amyloid-beta protein (A beta 42) in explicit water to characterize most plausible aggregation-prone structure (APS) for the monomer and the very early conformational transitions for A beta 42 protein misfolding process in a lag phase. Monitoring the early sequential conformational transitions of A beta 42 misfolding in water, the APS for A beta 42 monomer is characterized by the observed correlation between the nonlocal backbone H-bond formation and the hydrophobic side-chain exposure. Characteristics on the nature of the APS of A beta 42 allow us to provide new insight into the higher aggregation propensity of A beta 42 over A beta 40, which is in agreement with the experiments. On the basis of the structural features of APS, we propose a plausible aggregation mechanism from APS of A beta 42 to form fibril. The structural and mechanistic observations based on these simulations agree with the recent NMR experiments and provide the driving force and structural origin for the A beta 42 aggregation process to cause AD. (C) 2010 Wiley Periodicals, Inc. J Comput Chem 32: 349-355, 2011

The Notch signaling pathway appears to perform an important function in the determination of cell fate and in differentiation, in a wide variety of organisms and cell types. In this study, we provide evidence that the inactivation of Notch signaling by zinc is achieved via a PI3K-Akt-dependent, cytoplasmic retention of Notch1-IC and RBP-Jk. Extracellular zinc has been determined to inhibit constitutive active mutants of both Notch1 (Delta EN1) and Notch1-IC-mediated transcription. However, in such cases, neither the cleavage pattern of Notch nor the protein stability of Notch1-IC and RBP-Jk was found to have significantly changed. With regard to the modulation of Notch signaling, zinc appears to exert a significant negative influence on the binding occurring between Notch1 and RBP-Jk, both in vivo and in vitro. The zinc-induced inhibition of Notch signaling can be rescued via pretreatment with wortmannin or LY294002, both of which are specific PI3K signaling pathway inhibitors. Furthermore, we ascertained that zinc triggers the cytoplasmic retention of Notch1-IC and RBP-Jk, and that cytoplasmic retention could be rescued via treatment with wortmannin, Overall, we have determined that an important relationship exists between zinc and the Notch1 signaling pathway, and that this relationship is intimately involved with the cytoplasmic retention of Notch and RBP-Jk. (c) 2007 Elsevier Ireland Ltd. All rights reserved.