9 results on '"Barrow CJ"'
Search Results
2. Surface behavior and lipid interaction of Alzheimer beta-amyloid peptide 1-42: a membrane-disrupting peptide.
- Author
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Ambroggio EE, Kim DH, Separovic F, Barrow CJ, Barnham KJ, Bagatolli LA, and Fidelio GD
- Subjects
- Cell Membrane metabolism, Cholesterol chemistry, Fluorescent Dyes pharmacology, Humans, Ions, Kinetics, Lipid Bilayers, Microscopy, Confocal, Oxidative Stress, Phosphatidylcholines chemistry, Pressure, Protein Binding, Sphingomyelins chemistry, Surface Properties, Temperature, Alzheimer Disease metabolism, Amyloid beta-Peptides chemistry, Biophysics methods, Lipids chemistry, Peptide Fragments chemistry, Peptides chemistry
- Abstract
Amyloid aggregates, found in patients that suffer from Alzheimer's disease, are composed of fibril-forming peptides in a beta-sheet conformation. One of the most abundant components in amyloid aggregates is the beta-amyloid peptide 1-42 (Abeta 1-42). Membrane alterations may proceed to cell death by either an oxidative stress mechanism, caused by the peptide and synergized by transition metal ions, or through formation of ion channels by peptide interfacial self-aggregation. Here we demonstrate that Langmuir films of Abeta 1-42, either in pure form or mixed with lipids, develop stable monomolecular arrays with a high surface stability. By using micropipette aspiration technique and confocal microscopy we show that Abeta 1-42 induces a strong membrane destabilization in giant unilamellar vesicles composed of palmitoyloleoyl-phosphatidylcholine, sphingomyelin, and cholesterol, lowering the critical tension of vesicle rupture. Additionally, Abeta 1-42 triggers the induction of a sequential leakage of low- and high-molecular-weight markers trapped inside the giant unilamellar vesicles, but preserving the vesicle shape. Consequently, the Abeta 1-42 sequence confers particular molecular properties to the peptide that, in turn, influence supramolecular properties associated to membranes that may result in toxicity, including: 1), an ability of the peptide to strongly associate with the membrane; 2), a reduction of lateral membrane cohesive forces; and 3), a capacity to break the transbilayer gradient and puncture sealed vesicles.
- Published
- 2005
- Full Text
- View/download PDF
3. Diverse fibrillar peptides directly bind the Alzheimer's amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation.
- Author
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White AR, Maher F, Brazier MW, Jobling MF, Thyer J, Stewart LR, Thompson A, Gibson R, Masters CL, Multhaup G, Beyreuther K, Barrow CJ, Collins SJ, and Cappai R
- Subjects
- Amino Acid Sequence, Amyloid beta-Peptides classification, Amyloid beta-Peptides pharmacology, Amyloid beta-Protein Precursor ultrastructure, Animals, Astrocytes drug effects, Astrocytes metabolism, Cell Survival physiology, Cells, Cultured, Humans, Immunoblotting methods, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia drug effects, Microglia metabolism, Microscopy, Electron methods, Nerve Tissue Proteins ultrastructure, Neurons drug effects, Neurons ultrastructure, Peptide Fragments pharmacology, Prions classification, Prions pharmacology, Protein Binding, Recombinant Proteins, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Amyloid beta-Protein Precursor metabolism, Nerve Tissue Proteins metabolism, Neurons metabolism
- Abstract
The Alzheimer's disease Abeta peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Abeta and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-beta (Abeta), the fibrillar prion peptides PrP106-126 and PrP178-193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. Specificity was shown by a lack of change to amyloid precursor-like protein 1, tau-1 and cellular prion protein (PrP(c)) levels. APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that PrP106-126 and the non-toxic but fibril-forming PrP178-193 increased APP levels in cultures derived from both wild-type and PrP(c)-deficient mice indicating that fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and irrespective of parental protein expression. Fibrillar PrP106-126 and Abeta peptides bound recombinant APP and APLP2 suggesting the accumulation of these proteins was mediated by direct binding to the fibrillated peptide. This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18-146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders.
- Published
- 2003
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4. Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits.
- Author
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Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, and Barnham KJ
- Subjects
- Allosteric Regulation, Cell Membrane metabolism, Circular Dichroism, Electron Spin Resonance Spectroscopy, Humans, Nuclear Magnetic Resonance, Biomolecular, Oxidation-Reduction, Protein Binding, Spin Labels, Superoxide Dismutase chemistry, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Copper metabolism, Superoxide Dismutase metabolism, Zinc metabolism
- Abstract
Amyloid beta peptide (Abeta) is the major constituent of extracellular plaques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Cu(2+) and Zn(2+) bind Abeta, inducing aggregation and giving rise to reactive oxygen species. These reactions may play a deleterious role in the disease state, because high concentrations of iron, copper, and zinc have been located in amyloid in diseased brains. Here we show that coordination of metal ions to Abeta is the same in both aqueous solution and lipid environments, with His(6), His(13), and His(14) all involved. At Cu(2+)/peptide molar ratios >0.3, Abeta coordinated a second Cu(2+) atom in a highly cooperative manner. This effect was abolished if the histidine residues were methylated at N(epsilon)2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dismutase. Addition of Cu(2+) or Zn(2+) to Abeta in a negatively charged lipid environment caused a conformational change from beta-sheet to alpha-helix, accompanied by peptide oligomerization and membrane penetration. These results suggest that metal binding to Abeta generated an allosterically ordered membrane-penetrating oligomer linked by superoxide dismutase-like bridging histidine residues.
- Published
- 2001
- Full Text
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5. The amyloid-beta peptide and its role in Alzheimer's disease.
- Author
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Clippingdale AB, Wade JD, and Barrow CJ
- Subjects
- Amino Acid Sequence, Animals, Circular Dichroism, Humans, Magnetic Resonance Spectroscopy, Models, Biological, Models, Chemical, Molecular Sequence Data, Protein Binding, Protein Isoforms, Protein Structure, Secondary, Protein Structure, Tertiary, Alzheimer Disease metabolism, Amyloid beta-Peptides chemistry, Amyloid beta-Peptides physiology, Peptides chemistry, Peptides physiology
- Abstract
Amyloid formation plays a central role in the cause and progression of Alzheimer's disease. The major component of this amyloid is the amyloid-beta (A beta) peptide, which is currently the subject of intense study. This review discusses some recent studies in the area of A beta synthesis, purification and structural analysis. Also discussed are proposed mechanisms for A beta-induced neurotoxicity and some recent advances in the development of A beta-related therapeutic strategies.
- Published
- 2001
- Full Text
- View/download PDF
6. Homocysteine potentiates copper- and amyloid beta peptide-mediated toxicity in primary neuronal cultures: possible risk factors in the Alzheimer's-type neurodegenerative pathways.
- Author
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White AR, Huang X, Jobling MF, Barrow CJ, Beyreuther K, Masters CL, Bush AI, and Cappai R
- Subjects
- Alzheimer Disease physiopathology, Animals, Cell Survival drug effects, Cells, Cultured, Cerebral Cortex cytology, Dose-Response Relationship, Drug, Drug Synergism, Homocysteine blood, Humans, Kinetics, Mice, Mice, Inbred Strains, Neurons cytology, Risk Factors, Alzheimer Disease pathology, Amyloid beta-Protein Precursor toxicity, Copper toxicity, Homocysteine toxicity, Neurons drug effects, Neurotoxins toxicity
- Abstract
Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as reflected by the inhibition of toxicity with the Cu (I)-specific chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Abeta/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote significant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions.
- Published
- 2001
- Full Text
- View/download PDF
7. Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimer's disease.
- Author
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Liu ST, Howlett G, and Barrow CJ
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Amyloid beta-Peptides chemistry, Animals, Cations, Divalent chemistry, Cations, Divalent metabolism, Chelating Agents chemistry, Chelating Agents metabolism, Chromatography, High Pressure Liquid, Circular Dichroism, Dose-Response Relationship, Drug, Histidine chemistry, Humans, Molecular Sequence Data, Peptide Fragments chemistry, Peptide Fragments metabolism, Protein Structure, Secondary, Rats, Solutions, Zinc chemistry, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Histidine metabolism, Zinc metabolism
- Abstract
Metal ions such as Zn(2+) and Cu(2+) have been implicated in both the aggregation and neurotoxicity of the beta-amyloid (Abeta) peptide that is present in the brains of Alzheimer's sufferers. Zinc ions in particular have been shown to induce rapid aggregation of Abeta. Rat Abeta binds zinc ions much less avidly than human Abeta, and rats do not form cerebral Abeta amyloid. Rat Abeta differs from human Abeta by the substitution of Gly for Arg, Phe for Tyr, and Arg for His at positions 5, 10, and 13, respectively. Through the use of synthetic peptides corresponding to the first 28 residues of human Abeta, rat Abeta, and single-residue variations, we use circular dichroism spectroscopy, sedimentation assays, and immobilized metal ion affinity chromatography to show that the substitution of Arg for His-13 is responsible for the different Zn(2+)-induced aggregation behavior of rat and human Abeta. The coordination of Zn(2+) to histidine-13 is critical to the zinc ion induced aggregation of Abeta.
- Published
- 1999
- Full Text
- View/download PDF
8. On-line high-performance liquid chromatography/mass spectrometric investigation of amyloid-beta peptide variants found in Alzheimer's disease.
- Author
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Thompson AJ, Lim TK, and Barrow CJ
- Subjects
- Amino Acid Sequence, Amyloid beta-Peptides genetics, Chromatography, High Pressure Liquid methods, Genetic Variation, Humans, Mass Spectrometry methods, Molecular Sequence Data, Online Systems, Peptide Fragments chemical synthesis, Peptide Fragments chemistry, Peptides chemistry, Alzheimer Disease metabolism, Amyloid beta-Peptides chemical synthesis, Amyloid beta-Peptides chemistry, Peptides chemical synthesis
- Abstract
Abeta peptides are the major components of amyloid deposits in Alzheimer's disease. The presence of N-terminally truncated Abeta variants in amyloid may be a critical factor in Alzheimer's disease pathogenesis. These Abeta variants are less soluble and more amyloidogenic than full-length Abeta, making their separation, purification and identification difficult. High-performance liquid chromatography (HPLC) at elevated temperatures, coupled to electrospray ionization (ES) mass spectrometry (MS), enables rapid separation and identification of N-terminally truncated Abeta variants. This methodology provides a potential tool for exploring the importance of these Abeta variants in both the pathogenesis and diagnosis of Alzheimer's disease., (Copyright 1999 John Wiley & Sons, Ltd.)
- Published
- 1999
- Full Text
- View/download PDF
9. Solution structures of beta peptide and its constituent fragments: relation to amyloid deposition.
- Author
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Barrow CJ and Zagorski MG
- Subjects
- Amino Acid Sequence, Circular Dichroism, Humans, In Vitro Techniques, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Peptides chemistry, Protein Conformation, Alzheimer Disease pathology, Amyloid beta-Peptides chemistry
- Abstract
The secondary structures in solution of the synthetic, naturally occurring, amyloid beta peptides, residues 1 to 42 [beta (1-42)] and beta (1-39), and related fragments, beta (1-28) and beta (29-42), have been studied by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopy. In patients with Alzheimer's disease, extracellular amyloid plaque core is primarily composed of beta (1-42), whereas cerebrovascular amyloid contains the more soluble beta (1-39). In aqueous trifluoroethanol solution, the beta (1-28), beta (1-39), and beta (1-42) peptides adopt monomeric alpha-helical structures at both low and high pH, whereas at intermediate pH (4 to 7) an oligomeric beta structure (the probable structure in plaques) predominates. Thus, beta peptide is not by itself an insoluble protein (as originally thought), and localized or normal age-related alterations of pH may be necessary for the self-assembly and deposition of beta peptide. The hydrophobic carboxyl-terminal segment, beta(29-42), exists exclusively as an oligomeric beta sheet in solution, regardless of differences in solvent, pH, or temperature, suggesting that this segment directs the folding of the complete beta (1-42) peptide to produce the beta-pleated sheet found in amyloid plaques.
- Published
- 1991
- Full Text
- View/download PDF
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