Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's disease

Hilbich, Caroline; Kisters‐Woike, Brigitte; Reed, Jennifer; Masters, Colin L.; Beyreuther, Konrad

doi:10.1016/0022-2836(91)90881-6

Cited by 580 publications

(489 citation statements)

References 26 publications

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“…The mechanism of assembly suggested by the kinetics is consistent with literature data. In this model, soluble p(1-40) exists as dimers in dilute solution and at pH <3 (Hilbich et al, 1991). At higher pHs and concentrations it is interpreted by Tomski and Murphy (1992) to rapidly form tetramers of dimers (octamers), which can be thought of as protofilaments.…”

Section: Discussionmentioning

confidence: 99%

Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution

LeVine¹

1993

Protein Science

2,130

1,811

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Thioflavine T (ThT) associates rapidly with aggregated fibrils of the synthetic PjACderived peptides p( 1-28) and p(1-40), giving rise to a new excitation (ex) (absorption) maximum at 450 nm and enhanced emission (em) at 482 nm, as opposed to the 385 nm (ex) and 445 nrn (em) of the free dye. This change is dependent on the aggregated state as monomeric or dimeric peptides do not react, and guanidine dissociation of aggregates destroys the signal. There was no effect of high salt concentrations. Binding to the p(1-40) is of lower affinity, Kd 2 p M , while it saturates with a Kd of 0.54 pM for p(1-28). Insulin fibrils converted to a P-sheet conformation fluoresce intensely with ThT. A variety of polyhydroxy, polyanionic, or polycationic materials fail to interact or impede interaction with the amyloid peptides. This fluorometric technique should allow the kinetic elucidation of the amyloid fibril assembly process as well as the testing of agents that might modulate their assembly or disassembly.Keywords: P/A4; dye fluorescence; pH dependence Amyloid was defined by Virchow (1855) on the basis of a blue staining reaction with iodine (starch-like) followed by treatment with acid. ThS and ThT, (structure in Fig. 1A) characteristically stain amyloid-like deposits in a number of pathophysiological conditions (Vassar and Culling, 1959;KelCnyi, 1967). Along with Congo red they are believed to specifically interact in some unknown way with the crossed-0-sheet structure common to amyloid structures comprised of different materials. Naiki et al. (1989Naiki et al. ( , 1990Naiki et al. ( , 1991 have described the interaction of these dyes with amyloid proteins derived from serum amyloid A protein and apoAII to give enhanced fluorescence emission. The work described in this manuscript documents a similar phenomenon for interactions with aggregated species of synthetic peptides (Fig. 1B) whose sequences are derived from a protein (0/A4) isolated from deposits

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Section: Discussionmentioning

confidence: 99%

Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution

LeVine¹

1993

Protein Science

2,130

1,811

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“…This process is irreversible and is a major complicating factor in determining solution conditions for NMR experiments. Relative solubilities of various PA4 fragments have previously been investigated in different media by Hilbich et al (1991). They found that the addition of organic solvents to buffered peptide solutions resulted in a gradual decrease in solubility.…”

Section: Behaviour Of the Fragment Peptides In Solutionmentioning

confidence: 99%

“…Hollosi et al (1989) have found the presence of an a-helix, p-sheet and P-turn, as well as random coil conformations. Hilbich et al (1991) report that secondary structural properties can change depending on the solvent medium. In hexafluoroisopropanol the a-helix structure appears to be stabilised, while in water a P-sheet structure predominates.…”

Section: Fig 6 Noe Maps For Ba4-(1-28)-peptide (Left) and [E22q]/?amentioning

confidence: 99%

Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch‐type hereditary cerebral haemorrhage with amyloidosis

Sorimachi

Craik

1994

European Journal of Biochemistry

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Amyloid deposition is a biochemical and histopathologic hallmark of various clinical forms of amyloidoses including Alzheimer's disease and the Dutch‐type hereditary cerebral haemorrhage with amyloidosis. The self‐aggregating peptides responsible for these irreversible deposits have been sequenced but the mechanisms involved in the aggregation processes are not well understood. In order to gain an understanding of the possible structures prior to self‐association, the extracellular fragment of the Alzheimer amyloid protein (βA4) responsible for the deposits (the ‘native’ fragment) and a mutant of this with a single residue substitution (which is responsible for deposits in the Dutch‐type amyloidosis) were examined by 1H‐NMR spectroscopy. Interproton distance constraints were derived from NMR experimental data and incorporated into tertiary structure calculations using a simulated annealing protocol. Solution conformations of the fragment peptides associated with the two forms of amyloidoses are presented and compared. Although in both peptides the existence of a mixture of conformations in equilibrium is likely, one such population of structures possesses a flexible N‐terminus and a well defined C‐terminal region. The latter region includes a helical segment and a terminal turn‐like structure. These structural features may be important for the basis of amyloid formation. Comparison of the calculated structures of the two peptides revealed a conformationally different region arising from the conservative substitution of Gln22 for Glu22. This region may be responsible for altered binding in the mutant peptide, giving rise to the clinically different form of amyloidosis.

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“…The fl/A4 amyloid protein in amyloid fibrils is organized into a cross-fl conformation in which the peptide backbone is perpendicular to the fiber axis [8]. Studies using synthetic peptides containing partial-and full-length sequences of fl/A4 amyloid protein have suggested that the physical properties of fl/A4 amyloid protein themselves are the causes of amyloid fibril assembly and the formation of insoluble aggregates [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Cross‐linking of a synthetic partial‐length (1–28) peptide of the Alzheimer β/A4 amyloid protein by transglutaminase

1993

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Cerebral deposits of iliA4 amyloid protein is a pathologic sign of Alzheimer's disease. A synthetic partial-length (I 28) peptide of this protein contains one glutamine and two lysine residues. Here we show that this peptide can be a substrate oftransglutaminase, which catalyzes cross-linking between glutamine and lysine residues in peptides, by demonstrating the formation of multimeric peptides due to the action of this enzyme. A modified (Lys 2s to L-norleucine) version of the synthetic peptide was also cross-linked, but another modified version (Lys ~6 to L-norleucine) was very poorly cross-linked, indicating that Lys 16 is involved exclusively in the cross-linking of the partial-length peptide catalyzed by transglutaminase.Transglutaminase; Amyloid beta-protein; Alzheimer's disease.

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Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's disease

Cited by 580 publications

References 26 publications

Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution

Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution

Structure determination of extracellular fragments of amyloid proteins involved in Alzheimer's disease and Dutch‐type hereditary cerebral haemorrhage with amyloidosis

Cross‐linking of a synthetic partial‐length (1–28) peptide of the Alzheimer β/A4 amyloid protein by transglutaminase

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