11
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Glycation affects fibril formation of Aβ peptides

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Increasing evidence shows that β-amyloid (Aβ) peptides, which are associated with Alzheimer disease (AD), are heavily glycated in patients, suggesting a role of this irreversible nonenzymatic post-translational modification in pathology. Previous reports have shown that glycation increases the toxicity of the Aβ peptides, although little is known about the mechanism. Here, we used the natural metabolic by-product methylglyoxal as a glycating agent and exploited various spectroscopic methods and atomic force microscopy to study how glycation affects the structures of the Aβ40 and Aβ42 peptides, the aggregation pathway, and the morphologies of the resulting aggregates. We found that glycation significantly slows down but does not prevent β-conversion to mature fibers. We propose that the previously reported higher toxicity of the glycated Aβ peptides could be explained by a longer persistence in an oligomeric form, usually believed to be the toxic species.

          Related collections

          Most cited references46

          • Record: found
          • Abstract: found
          • Article: not found

          Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose.

          The glycation of proteins by glucose has been linked to the development of diabetic complications and other diseases. Early glycation is thought to involve the reaction of glucose with N-terminal and lysyl side chain amino groups to form Schiff's base and fructosamine adducts. The formation of the alpha-oxoaldehydes, glyoxal, methylglyoxal and 3-deoxyglucosone, in early glycation was investigated. Glucose (50 mM) degraded slowly at pH 7.4 and 37 degrees C to form glyoxal, methylglyoxal and 3-deoxyglucosone throughout a 3-week incubation period. Addition of t-BOC-lysine and human serum albumin increased the rate of formation of alpha-oxoaldehydes - except glyoxal and methylglyoxal concentrations were low with albumin, as expected from the high reactivity of glyoxal and methylglyoxal with arginine residues. The degradation of fructosyl-lysine also formed glyoxal, methylglyoxal and 3-deoxyglucosone. alpha-Oxoaldehyde formation was dependent on the concentration of phosphate buffer and availability of trace metal ions. This suggests that alpha-oxoaldehydes were formed in early glycation from the degradation of glucose and Schiff's base adduct. Since alpha-oxoaldehydes are important precursors of advanced glycation adducts, these adducts may be formed from early and advanced glycation processes. Short periods of hyperglycaemia, as occur in impaired glucose tolerance, may be sufficient to increase the concentrations of alpha-oxoaldehydes in vivo.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain.

            The major components of neuritic plaques found in Alzheimer disease (AD) are peptides known as amyloid beta-peptides (Abeta), which derive from the proteolitic cleavage of the amyloid precursor proteins. In vitro Abeta may undergo a conformational transition from a soluble form to aggregated, fibrillary beta-sheet structures, which seem to be neurotoxic. Alternatively, it has been suggested that an alpha-helical form can be involved in a process of membrane poration, which would then trigger cellular death. Conformational studies on these peptides in aqueous solution are complicated by their tendency to aggregate, and only recently NMR structures of Abeta-(1-40) and Abeta-(1-42) have been determined in aqueous trifluoroethanol or in SDS micelles. All these studies hint to the presence of two helical regions, connected through a flexible kink, but it proved difficult to determine the length and position of the helical stretches with accuracy and, most of all, to ascertain whether the kink region has a preferred conformation. In the search for a medium which could allow a more accurate structure determination, we performed an exhaustive solvent scan that showed a high propensity of Abeta-(1-42) to adopt helical conformations in aqueous solutions of fluorinated alcohols. The 3D NMR structure of Abeta-(1-42) shows two helical regions encompassing residues 8-25 and 28-38, connected by a regular type I beta-turn. The surprising similarity of this structure, as well as the sequence of the C-terminal moiety, with those of the fusion domain of influenza hemagglutinin suggests a direct mechanism of neurotoxicity.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Dicarbonyl intermediates in the maillard reaction.

              The complexity of the Maillard reaction arises partly from multiple fragmentation reactions of the sugar moiety, constituting branch points in the reaction progress and establishing many parallel reaction pathways. Reactive intermediates produced by these processes are often alpha-oxoaldehydes. The formation of alpha-oxoaldehydes enhances and redirects glycating activity in the Maillard reaction since alpha-oxoaldehydes are up to 20,000-fold more reactive than glucose in glycation processes and are predominantly arginine-directed glycating agents. alpha-Oxoaldehydes bypass a requirement for a fructosamine precursor in the formation of advanced glycation end products (AGEs) since alpha-oxoaldehydes react with proteins (also nucleotides and basic phospholipids) to form AGEs directly. The major AGE formed from alpha-oxoaldehydes is generally a hydroimidazolone with other products-although for glyoxal, N(omega)-carboxymethylarginine is a major product. alpha-Oxoaldehyde formation also occurs in the absence of an amine substrate, particularly during heat processing of sugar solutions and lipid peroxidation processes-in the latter case, the glycation adducts are advanced lipoxidation products (ALEs). Hydroimidazolones are quantitatively important AGEs in cellular and extracellular proteins in physiological systems. Hydroimidazolone free adducts are liberated by cellular proteolysis and digestion. They are released into blood plasma for urinary excretion. Modification of arginine residues by alpha-oxoaldehydes may be particularly damaging since arginine residues have high-frequency occurrence in ligand and substrate recognition sites in receptor and enzyme active sites. Along with fructosamine formation, alpha-oxoaldehyde intermediates of the Maillard reaction represent a major source of damage to the proteome and genome.
                Bookmark

                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                0021-9258
                1083-351X
                24 August 2018
                29 June 2018
                29 June 2018
                : 293
                : 34
                : 13100-13111
                Affiliations
                From the []Department of Chemical Sciences, University of Naples Federico II, via Cintia, Napoli 80126, Italy,
                [§ ]King's College London and UK Dementia Research Institute at King's College London, Denmark Hill Campus, London SE5 9RT, United Kingdom,
                []Universita' di Salerno, 84084 Fisciano, Italy,
                the []Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy,
                the [** ]London Centre for Nanotechnology, University College London, London WC1H 0AH, United Kingdom, and
                the [‡‡ ]Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
                Author notes
                [2 ] To whom correspondence may be addressed: Dept. of Chemical Sciences, University of Naples Federico II, via Cintia, Napoli 80126, Italy. E-mail: delia.picone@ 123456unina.it .
                [3 ] Supported by a Diabetes UK and a Dementia Research Institute grant. To whom correspondence may be addressed: King's College London, Denmark Hill Campus, London SE5 9RT, United Kingdom. E-mail: annalisa.pastore@ 123456crick.ac.uk .
                [1]

                Both authors contributed equally to this work.

                Edited by Paul E. Fraser

                Author information
                https://orcid.org/0000-0002-7582-2581
                https://orcid.org/0000-0002-3047-654X
                Article
                RA118.002275
                10.1074/jbc.RA118.002275
                6109928
                29959224
                9154bb8f-ff9b-4cbf-9152-327f8e190d87
                © 2018 Emendato et al.

                Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license.

                History
                : 5 February 2018
                : 6 June 2018
                Categories
                Molecular Biophysics

                Biochemistry
                alzheimer disease,glycobiology,structural biology,carbohydrate,aggregation,carbohydrates,glycation,protein aggregation,fibril formation,neurodegeneration,beta-amyloid,glycosylation,amyloid plaques

                Comments

                Comment on this article