Characterizing affinity epitopes between prion protein and β-amyloid using an epitope mapping immunoassay

Cellular prion protein, a membrane protein, is expressed in all mammals. Prion protein is also found in human blood as an anchorless protein, and this protein form is one of the many potential sources of misfolded prion protein replication during transmission. Many studies have suggested that β-amyloid_1–42 oligomer causes neurotoxicity associated with Alzheimer''s disease, which is mediated by the prion protein that acts as a receptor and regulates the hippocampal potentiation. The prevention of the binding of these proteins has been proposed as a possible preventative treatment for Alzheimer''s disease; therefore, a greater understanding of the binding hot-spots between the two molecules is necessary. In this study, the epitope mapping immunoassay was employed to characterize binding epitopes within the prion protein and complementary epitopes in β-amyloid. Residues 23–39 and 93–119 in the prion protein were involved in binding to β-amyloid_1–40 and _1–42, and monomers of this protein interacted with prion protein residues 93–113 and 123–166. Furthermore, β-amyloid antibodies against the C-terminus detected bound β-amyloid_1–42 at residues 23–40, 104–122 and 159–175. β-Amyloid epitopes necessary for the interaction with prion protein were not determined. In conclusion, charged clusters and hydrophobic regions of the prion protein were involved in binding to β-amyloid_1–40 and _1–42. The 3D structure appears to be necessary for β-amyloid to interact with prion protein. In the future, these binding sites may be utilized for 3D structure modeling, as well as for the pharmaceutical intervention of Alzheimer''s disease.     

Synthesis of Symmetrical and Unsymmetrical Ureas Using Unsymmetrical Diaryl Carbonates

Appropriately substituted unsymmetrical diaryl carbonates react smoothly with primary amines to give the carbamates derived by nucleophilic displacement of the less electron rich aromatic substituent. Subsequent treatment of the carbamates with primary and secondary amines gives either symmetrical or unsymmetrical ureas in excellent yield and the overall process can be carried out as a “one pot” operation. Acetonitrile is the preferred solvent and addition of DBU facilitates the carbamate → urea transformation.     

Acetylcholinesterase inhibitors: Modeling potential candidates

Alzheimer's disease is the leading cause of dementia for elderly people. The main active therapeutic is supported on the increased levels of acetylcholine in the synaptic cleft, based on reversible inhibition of the acetylcholinesterase (AChE) enzyme. This article aims to propose possible inhibitor candidates for AChE, designed from nonisoprenoid lipids of cashew (Anacardium occidentale), and based on several electronic properties. These electronic properties were obtained through B3LYP/6‐311+G(2d,p) calculation level. Principal component analysis reveals that from the set of studied molecular structures a small group is correlated with donepezil, a drug with known biological activity. © 2012 Wiley Periodicals, Inc.     

Structure-based study of antiamyloidogenic cyclic d,l-α-peptides

Protein misfolding and aggregation are the hallmarks of many devastating diseases. We have previously shown that cyclic d,l-α-peptide CP-2 reacts and stabilizes less toxic forms of amyloid β (Aβ), and protects the cells from Aβ-induced toxicity. Here, we performed extensive structure-based studies on CP-2 to elucidate the contribution of each residue to the total antiamyloidogenic activity and determine the interactions that are involved between CP-2 and Aβ. We showed that the hydrophobicity of CP-2 analogs correlates with their antiamyloidogenic potency, however, aromatic interactions are even more important for this activity. The antiamyloidogenic activity of CP-2 analogs also correlates with their ability to self-assemble, as shown by the critical micelle concentration measurements. The cell survival studies performed on rat pheochromocytoma PC-12 cells suggest that incorporation of an additional aromatic residue to the CP-2's sequence increases its protective effect against Aβ42-induced toxicity.     

阿尔茨海默症病理机制中的金属代谢和金属药物

随着人口老龄化进程的发展,阿尔茨海默症(AD)已成为威胁中国和世界人口健康和经济的重大疾病.本文综述了近年来AD病理的分子机制的新进展,分析了其中金属代谢的意义.研究发现,在AD进程中,围绕淀粉样斑块(AP)和神经缠绕斑(NFT)的形成,多因素相互联系并发挥作用,这些主要因素包括金属内稳态、胰岛素抵抗、神经炎症、线粒体和血脑屏障改变等.与AD病理过程密切相关的主要蛋白质均参与了金属元素的生理代谢过程,而细胞金属离子的内稳态失衡加剧了AD病理的恶化.金属药物在AD诊断和治疗中可能具有以下的发展潜力:(1)AD早期诊断探针;(2)调节金属内稳态的配体和/或微量元素补充;(3)抗糖尿病金属配合物;(4)神经元和血脑屏障(BBB)保护金属药物.     

Bioelectrochemistry for various facets of tau protein biochemistry

Tau protein undergoes complex biochemical processes involved in normal and diseased cellular functions; specifically, tau pathology has been linked to neurodegeneration. At the heart of tau biochemistry are three pillars: microtubules, phosphorylation, and aggregation. However, these three processes are also regulated through other biomolecules in the biological setting, such as metal ions and small and larger ligands, including proteins and nucleic acids. This review describes the latest electrochemical approaches toward greater understanding of tau biochemistry, early disease diagnosis, and drug inhibitor screening.     

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray–Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.     

Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases

The generation of highly organized amyloid fibrils is associated with a wide range of conformational pathologies, including primarily neurodegenerative diseases. Such disorders are characterized by misfolded proteins that lose their normal physiological roles and acquire toxicity. Recent findings suggest that proteostasis network impairment may be one of the causes leading to the accumulation and spread of amyloids. These observations are certainly contributing to a new focus in anti‐amyloid drug design, whose efforts are so far being centered on single‐target approaches aimed at inhibiting amyloid aggregation. Chaperones, known to maintain proteostasis, hence represent interesting targets for the development of novel therapeutics owing to their potential protective role against protein misfolding diseases. In this minireview, research on nanoparticles that can either emulate or help molecular chaperones in recognizing and/or correcting protein misfolding is discussed. The nascent concept of “nanochaperone” may indeed set future directions towards the development of cost‐effective, disease‐modifying drugs to treat several currently fatal disorders.     

Tacrines as Therapeutic Agents for Alzheimer's Disease. V. Recent Developments

Herein we have reviewed our recent developments for the identification of new tacrine analogues for Alzheimer's disease (AD) therapy. Tacrine, the first cholinesterase inhibitor approved for AD treatment, did not stop the progression of AD, producing only some cognitive improvements, but exhibited secondary effects mainly due to its hepatotoxicity. Thus, the drug was withdrawn from the clinics administration. Since then, many publications have described non‐hepatotoxic tacrines, and in addition, important efforts have been made to design multitarget tacrines by combining their cholinesterase inhibition profile with the modulation of other biological targets involved in AD.     

Extract from the Marine Seaweed Padina pavonica Protects Mitochondrial Biomembranes from Damage by Amyloidogenic Peptides

The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed Padina pavonica (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer’s disease (AD) and Parkinson’s disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome c from the mitochondria. Using cardiolipin-enriched synthetic lipid membranes, we also show that dye leakage from fluorophore-loaded vesicles and formation of channel-like pores in planar bilayer membranes are largely prevented by incubating the oligomeric aggregates with PPE. Lastly, we demonstrate that PPE curtails the ability of Aβ42 and α-syn monomers to self-assemble into larger β-aggregate structures, as well as potently disrupts their respective amyloid fibrils. In conclusion, the mito-protective and anti-aggregator biological activities of Padina pavonica extract may be of therapeutic value in neurodegenerative proteinopathies, such as AD and PD.