The amyloid- peptide (A) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of A polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger A assemblies may even increase oligomerderived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of A in an ␣-helical conformation, inspired by the postulated A native structure. This is achieved with 2 different classes of compounds that also reduce A toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human A 1-42 in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central A ␣-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of A polymerization.amyloid fibrils ͉ neurodegenerative disease ͉ protein misfolding ͉ Alzheimer's disease A lzheimer's disease is a progressive neurodegenerative disorder that is characterized by cerebral extracellular amyloid plaques and intracellular neurofibrillary tangles (1). Classically, the amyloid cascade hypothesis (2) states that Alzheimer's disease is caused by fibril and plaque formation of amyloid- peptide (A) in the central nervous system. More recently, the hypothesis has been modified to include A assemblies of sizes intermediate to monomeric and fibrillar forms, which today are considered to be the main source of cytotoxicity (3). Such A assemblies include low-number oligomers and larger assemblies known as protofibrils, globulomers, Alzheimer's disease diffusible ligands, or A*56 (4-7). A is cleaved from an integral membrane protein, the amyloid  precursor protein (APP), predominantly as a 40-residue peptide (A 1-40 ). In addition, a C-terminally elongated 42-residue version can be excised (A 1-42 ); it is this longer variant that is the main constituent of parenchymal amyloid deposits (8).The link between A aggregation and Alzheimer's disease implies that inhibitors of this process should be able to slow down disease progression. A number of low-molecular-mass A aggregation inhibitors have been identified by use of screens of compound libraries as well as rational design strategies. The resulting inhibitors include such chemically diverse compounds as curcumin, inositol, and nicotine (9, 10). The screens have identified inhibitors of fibril formation that similarly to the rationally designed inhibitors are predicted to bind to A in an elongated, -strand-like conformation and prevent its polymerization. A potential problem with this strategy is that blocking the later stages of fibril formation will favor t...
Alzheimer's disease (AD), an age related neurodegenerative disorder, threatens to become a major health-economic problem. Assembly of 40- or 42-residue amyloid beta-peptides (Abeta) into neurotoxic oligo-/polymeric beta-sheet structures is an important pathogenic feature in AD, thus, inhibition of this process has been explored to prevent or treat AD. The C-terminal part plays an important role in Abeta aggregation, but most Abeta aggregation inhibitors have targeted the central region around residues 16-23. Herein, we synthesized hexapeptides with varying extents of N-methylation based on residues 32-37 of Abeta, to target its C-terminal region. We measured the peptides' abilities to retard beta-sheet and fibril formation of Abeta and to reduce Abeta neurotoxicity. A penta-N-methylated peptide was more efficient than peptides with 0, 2, or 3 N-methyl groups. This penta-N-methylated peptide moreover increased life span and locomotor activity in Drosophila melanogaster flies overexpressing human Abeta(1-42).
Background: Although the identification and characterization of several fish allergens have already been reported, there is almost no data on Indian fish allergens and the effect of thermal processing on their allergenicity. This study aimed at the evaluation of the changes in the level of allergenicity of 4 highly consumed Indian fishes, i.e. pomfret, hilsa, bhetki and mackerel, that occurred after boiling and frying. Methods: In this study 110 patients with fish hypersensitivity as evidenced by clinical history and symptoms were recruited based on their positive skin prick test results. The raw, boiled and fried muscle extracts of the 4 fishes were prepared, and each extract was tested by ELISA and immunoblotting with patients’ sera. Results: ELISA and immunoblotting studies demonstrated that the raw muscle extracts of pomfret, hilsa, bhetki and mackerel were allergenic. While the allergenicity of boiled and fried extracts of pomfret and hilsa was considerably reduced, maximum allergenicity of bhetki was demonstrated in the fried extract. The degree of allergenicity of bhetki was demonstrated in the order fried > boiled > raw while that of mackerel followed the order raw > boiled ≃ fried. Conclusion: The specificIgE-binding activity and immunoblot profile clearly showed that pomfret and hilsa fish allergens are heat-labile, while allergens of bhetki and mackerel maintained strong reactivity even after thermal treatment.
The level of serum glycoproteins and their glycosylation pattern change in liver diseases including hepatocellular carcinoma (HCC). Some of them, especially alpha fetoprotein (AFP), serve as useful biomarkers for HCC. The present investigation showed high level of AFP in hepatitis B cirrhosis (HBV-LC) and hepatitis C cirrhosis (HCV-LC) patients. However, increase of AFP level was not significantly high in chronic hepatitis B (HBV-CH) as determined by ELISA using monoclonal anti-human AFP (mAb-AFP). The differential expression of sialic acid linkage was observed in HBV-CH and HCV-LC by ELISA; the former bound strongly with Sambucus nigra agglutinin (SNA), which has exclusive binding specificity for NeuAcα2-6-, whereas HCV-LC reacted preferably with Maackia amurensis agglutinin (MAA) which recognizes NeuAcα2-3-. There was significantly high glycan branching in HBV-LC and HCV-LC in comparison to controls as illustrated by concanavalin A. This was further confirmed by Phaseolus vulgaris erythroagglutinin (E-PHA) and Datura stramonium agglutinin (DSA). Enhanced fucosylation of AFP was observed in HBV-LC, HCV-LC and HCC patients by ELISA using fucose binding Aleuria aurantia lectin; however, maximum binding was found in HCC. Fucosylation with α1-6 linkage was further confirmed by Lens culinaris agglutinin (LCA). From the above results it is concluded that the changes in concentration of AFP, differential expression of sialic acid, increase of glycan branching and fucosylation have a prognostic value of hepatitis and it could be possible that lectin-based assay with AFP can aid in diagnosis of hepatitis diseases besides clinical examination and routine laboratory investigation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.