Fibrillogenesis of synthetic amyloid-β peptides is dependent on their initial secondary structure

Soto, Claudio; Castaño, Eduardo M.; Kumar, Rashmi; Beavis, Ronald C.; Frangione, Blas

doi:10.1016/0304-3940(95)12089-m

Cited by 144 publications

(104 citation statements)

References 19 publications

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“…2A) that indicate a high degree of motion on the sub-nanosecond time scale. This motion can arise from very rapid tumbling of the short A␤ peptide as well as its very dynamic structure (31)(32)(33). A more detailed study of soluble A␤ will be forthcoming.…”

Section: Fibril Formation Of R1-labeled A␤ Results In Significantmentioning

confidence: 99%

Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling

Török

Milton²,

Kayed³

et al. 2002

Journal of Biological Chemistry

362

129

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Electron paramagnetic resonance spectroscopy analysis of 19 spin-labeled derivatives of the Alzheimer's amyloid ␤ (A␤) peptide was used to reveal structural features of amyloid fibril formation. In the fibril, extensive regions of the peptide show an in-register, parallel arrangement. Based on the parallel arrangement and side chain mobility analysis we find the amyloid structure to be mostly ordered and specific, but we also identify more dynamic regions (N and C termini) and likely turn or bend regions (around residues 23-26). Despite their different aggregation properties and roles in disease, the two peptides, A␤40 and A␤42, homogeneously co-mix in amyloid fibrils suggesting that they possess the same structural architecture.Protein deposits are commonly associated with a wide range of degenerative diseases, including Alzheimer's disease, Parkinson's disease, type-2 diabetes, macular degeneration, and several others. These deposits contain a number of proteins that often have fibrillar morphology. In Alzheimer's disease, the extracellular deposits are largely made up of a short 39 -42-amino-acid-long peptide referred to as A␤.Like all other amyloid fibrils, A␤ fibrils are thought to have a cross ␤-structure, in which individual ␤-strands are organized roughly perpendicular to the fiber axis. According to fiber x-ray diffraction studies of A␤ fibrils (1, 2) the unit spacing between these individual ␤-strands along the fibril axis is 4.7 Å, while the sheets are spaced at about 10 Å. However, our understanding of the exact structure of A␤ or that of other amyloid fibrils is still very incomplete. For example, it is not known which regions of the peptide are directly involved in the formation of the cross ␤-structure. Simple geometric considerations suggest that not all amino acids in A␤40 or A␤42 can be part of the cross ␤-structure in a linear, fully extended ␤-strand. Assuming an average distance between residues in an extended ␤-strand of 3.5 Å per residue, a completely extended structure model predicts a minimum extended length of 140 Å for A␤40. This length is considerably larger than the diameter of the putative building blocks of the fibrils, protofilaments with an individual diameter of 40 -55 Å (3-6). In fact, it even exceeds the 60 -100-Å diameter of the entire fibril. Thus, turn or bend regions are needed to account for the fiber dimensions. Indeed, hydrogen-deuterium exchange measurements of fibrillar A␤ (7) suggest that only about half of the peptide is involved in a protective hydrogen-bonded structure. In addition, Fourier transform infrared spectroscopic studies on fibrils indicate the presence of at least one turn (8, 9). However, the locations of these turns or the location of the ␤-strands are still unclear.Furthermore, there has also been some controversy regarding the arrangement of individual peptides with respect to each other. Fourier transform infrared spectroscopic data indicate an antiparallel organization of the ␤-sheets within the A␤ fibril (8,10). An antiparallel organization is al...

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Section: Fibril Formation Of R1-labeled A␤ Results In Significantmentioning

confidence: 99%

Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling

Török

Milton²,

Kayed³

et al. 2002

Journal of Biological Chemistry

362

129

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“…Although this ratio may apparently depend , ,n the source of All and other conditions [30], it is clear hat only a small fraction of the immobilized AI] molecules are able to bind to apoE on the minute time scale, as followed hy SPR. These results confirm the importance of the confor~nation of A[3 on binding.…”

Section: Discussionmentioning

confidence: 99%

Interaction between human amphipathic apolipoproteins and amyloid β‐peptide: surface plasmon resonance studies

Shuvaev

Siest

1996

FEBS Letters

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Several apolipoproteins including apoE and apoA-I are known to be associated with amyloid ~peptide, a major component of senile plaques in Alzheimer's disease. In the present study the interaction between three human amphipathic apolipoproteins apoE3, apoA-I and apoA-1I and immobilized amyloid ~i-peptide (1-40) was quantified by plasmon resonance. The interactions were saturable and reversible. The results demonstrated a high affmity of the binding of amphipathic apolipoproteins to amyloid ~peptide. On the other hand, only a small population of synthetic amyloid ~peptide participated in the interaction. The apparent equilibrium dissociation constants /fD were 10 nM for apoE3, 25 nM for apoA-I and 80 nM for apoA-II under physiological conditions. The affinity of the apoE3-amyloid ~-peptide binding was not affected by pH in the range 6.0-8.0 but was significantly increased by high salt concentration. ApoA-I mainly followed similar patterns. A major participation of hydrophobic forces in the binding of apoE3 and apoA-I to amyloid ~-peptide was suggested.

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“…The longer that the -(1-42) peptide remains in aqueous acetonitrile solution, the more likely it will become an aggregated -sheet structure. Additionally, different commercially prepared batches of HPLC-purified -(1-42) peptides can have different starting aggregation states and structures (Soto et al, 1995b), which will then in turn affect their solubility, aggregation rates, biological activities in solution (Busciglio et al, 1992, Pike et al, 1993, Simmons et al, 1994, Wujek et al, 1996, and the ability to reproduce biophysical measurements.…”

Section: Sample Preparationmentioning

confidence: 99%

Nicotine Inhibits Amyloid Formation by the β-Peptide

et al. 1996

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The 42-residue -(1-42) peptide is the major protein component of amyloid plaque cores in Alzheimer's disease. In aqueous solution at physiological pH, the synthetic -(1-42) peptide readily aggregates and precipitates as oligomeric -sheet structures, a process that occurs during amyloid formation in Alzheimer's disease. Using circular dichroism (CD) and ultraviolet spectroscopic techniques, we show that nicotine, a major component in cigarette smoke, inhibits amyloid formation by the -(1-42) peptide. The related compound cotinine, the major metabolite of nicotine in humans, also slows down amyloid formation, but to a lesser extent than nicotine. In contrast, control substances pyridine and Nmethylpyrrolidine accelerate the aggregation process. Nuclear magnetic resonance (NMR) studies demonstrate that nicotine binds to the 1-28 peptide region when folded in an R-helical conformation. On the basis of chemical shift data, the binding primarily involves the N-CH 3 and 5′CH 2 pyrrolidine moieties of nicotine and the histidine residues of the peptide. The binding is in fast exchange, as shown by single averaged NMR peaks and the lack of nuclear Overhauser enhancement data between nicotine and the peptide in two-dimensional NOESY spectra. A mechanism is proposed, whereby nicotine retards amyloidosis by preventing an R-helix f -sheet conformational transformation that is important in the pathogenesis of Alzheimer's disease.

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Fibrillogenesis of synthetic amyloid-β peptides is dependent on their initial secondary structure

Cited by 144 publications

References 19 publications

Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling

Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling

Interaction between human amphipathic apolipoproteins and amyloid β‐peptide: surface plasmon resonance studies

Nicotine Inhibits Amyloid Formation by the β-Peptide

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