Characterizations of distinct amyloidogenic conformations of the Aβ (1–40) and (1–42) peptides (original) (raw)
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Several biophysical techniques have been used to determine differences in the aggregation profile (i.e., the secondary structure, aggregation propensity, dynamics, and morphology of amyloid structures) and the effects on cell viability of three variants of the amyloid b peptide involved in Alzheimer's disease. We focused our study on the Glu 22 residue, comparing the effects of freshly prepared samples and samples aged for at least 20 days. In the aged samples, a high propensity for aggre-gation and b-sheet secondary structure appears when residue 22 is capable of establishing polar (Glu 22 in wild-type) or hydro-phobic (Val 22 in E22V) interactions. The Arctic variant (E22G) presents a mixture of mostly disordered and a-helix structures (with low b-sheet contribution). Analysis of transmission electron micrographs and atomic force microscopy images of the peptide variants after aging showed significant quantitative and qualitative differences in the morphology of the formed aggregates. The effect on human neuroblastoma cells of these Ab 12-28 variants does not correlate with the amount of b-sheet of the aggregates. In samples allowed to age, the native sequence was found to have an insignificant effect on cell viability, whereas the Arctic variant (E22G), the E22V variant, and the slightly-aggregating control (F19G-F20G) had more prominent effects.
European Journal of Biochemistry, 1998
Alzheimer's β-amyloid peptide (Aβ) is a 39-to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Aβ plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21→Gly and Glu22→Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Aβ in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Aβ-(25Ϫ35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Aβ, forming the corresponding 23-, 21-and 19Ϫ35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6Ϫ10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to β sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from A helix and towards β sheet. In individuals with the Ala21→Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17Ϫ20 would be more amyloidogenic than the wild type homologues.
Amyloid-β peptide structure in aqueous solution varies with fragment size
The Journal of chemical physics, 2011
Phase diagram of polypeptide chains JCP: BioChem. Phys. 5, 11B602 (2011) Effects of surface interactions on peptide aggregate morphology JCP: BioChem. Phys. 5, 08B624 (2011) Effects of surface interactions on peptide aggregate morphology J. Chem. Phys. 135, 085102 (2011) Does amino acid sequence determine the properties of A dimer? J. Chem. Phys. 135, 035103 (2011) Additional information on J. Chem. Phys.
Conformational behavior and aggregation of amyloid beta peptides
2008
It is a great pleasure for me to acknowledge all the people who helped me to accomplish this dissertation. First and foremost, I wish to express my deep felt gratitude towards my supervisor, Prof. Dr. Alfons Geiger, for giving me an opportunity to work in their group. I am indebted for his advice, encouragement, easy accessibility and freedom for work which helped me to explore new ideas and to complete the work. I also thank Prof. Dr. Roland Winter for his helpful suggestions and nice discussions in group meetings. Thank you for being wonderful teachers! I am grateful to my coworkers, who ensured a technically stimulating, creative and pleasant working environment and helped in technical and non-technical matters. My special thanks to Dr. Ivan Brovchenko for his erudite assistance, which was in the completion of my work. Thank you very much Ivan! Oftenly, I had very nice discussions with Dr. Dietmar Paschek, Dr. Alla Oleinikova and other coworkers on technical and non-technical issues through which I learnt many things. Thank you all for giving nice company! I thank International Max-Planck Research School in Chemical Biology (IMPRS-CB) for providing me fellowship and for generous travel grants. I am grateful to IMPRS-CB faculty members for their valuable teaching and practical courses. My sincere thanks to Anneliese Ahlke and Dr. Jutta Rötter for their help in all administrative work. Danke schön Frau Ahlke und Jutta! I also appreciate generous computing time from LiDO. II Finally, I am thankful to those who have assisted me directly or indirectly in the completion of this work. Their assistance is invaluable and shall always be held in high regards. III 9 Temperature dependence of Aβ 7 and Aβ 7g peptides aggregations: REMD simulation study
Proteins: Structure, Function, and Bioinformatics, 2016
The histopathological hallmark of Alzheimer's disease (AD) is the aggregation and accumulation of the amyloid beta peptide (Ab) into misfolded oligomers and fibrils. Here we examine the biophysical properties of a protective Ab variant against AD, A2T, and a causative mutation, A2V, along with the wild type (WT) peptide. The main finding here is that the A2V native monomer is more stable than both A2T and WT, and this manifests itself in different biophysical behaviors: the kinetics of aggregation, the initial monomer conversion to an aggregation prone state (primary nucleation), the abundances of oligomers, and extended conformations. Aggregation reaction modeling of the conversion kinetics from native monomers to fibrils predicts the enhanced stability of the A2V monomer, while ion mobility spectrometry-mass spectrometry measures this directly confirming earlier predictions. Additionally, unique morphologies of the A2T aggregates are observed using atomic force microscopy, providing a basis for the reduction in long term potentiation inhibition of hippocampal cells for A2T compared with A2V and the wild type (WT) peptide. The stability difference of the A2V monomer and the difference in aggregate morphology for A2T (both compared with WT) are offered as alternate explanations for their pathological effects.
Biochemical and Biophysical Research Communications, 2005
The effects of D-amino acids at Asp 23 and Ser 26 residues on the conformational preference of b-amyloid (Ab) peptide fragment (Ab 20-29 ) have been studied using different spectroscopic techniques, namely vibrational circular dichroism (VCD), vibrational absorption, and electronic circular dichroism. To study the structure of the Ab 20-29 , [D-Asp 23 ]Ab 20-29 , and [D-Ser 26 ]Ab 20-29 peptides under different conditions, the spectra were measured in 10 mM acetate buffer (pH 3) and in 2,2,2-trifluoroethanol (TFE). The spectroscopic results indicated that at pH 3, Ab 20-29 peptide takes random coil with b-turn structure, while [D-Ser 26 ]Ab 20-29 peptide adopts significant amount of polyproline II (PPII) type structure along with b-turn contribution and D-Asp-substituted peptide ([D-Asp 23 ]Ab 20-29 ) adopts predominantly PPII type structure. The increased propensity for PPII conformation upon D-amino acid substitution, in acidic medium, has important biological implications. In TFE, Ab 20-29 , [D-Asp 23 ]Ab 20-29 , and [D-Ser 26 ]Ab 20-29 peptides adopt 3 10 -helix, a-helix, and random coil with some b-turn structures, respectively. The VCD data obtained for the Ab peptide films suggested that the secondary structures for the peptide films are not the same as those for corresponding solution and are also different among the Ab peptides studied here. This observation suggests that dehydration can have a significant influence on the structural preferences of these peptides.