Structure of Amyloid A4‐(1–40)‐Peptide of Alzheimer's Disease

Abstract

One of the principal peptide components of the amyloid plaque deposits of Alzheimer's disease in humans is the 40-amino-acid peptide 8-amyloid A4-( 1 -40)-peptide. The full-length A4-( I -40)-peptide was chemically synthesized and the solution structure determined by two-dimensional nuclear magnetic resonance spectroscopy and restrained molecular-dynamics calculations. Synthetic human A4-( 1 -40)-peptide was soluble and non-aggregating for several days in 40 % (by vol.) trifluoroethanol/water. All spin systems could be unambiguously assigned, and a total of 203 sequential and medium-range crosspeaks were found in the NOESY (nuclear Overhauser enhancement spectroscopy) spectrum. Long-range NOE cross-peaks that would indicate tertiary structure of the peptide were absent. The main secondarystructure elements found by chemical-shift analysis, sequential and medium-range NOESY data, and NOE-based restrained molecular-dynamics calculations were two helices, Glnl5 -Asp23 and Ile31-Met35, whereas the rest of the peptide was in random-coil conformation. A similar secondary structure is suggested for the aggregation part of prions, the postulated causative agents of the transmissible spongiform encephalopathy. The sequence of the helical part of prion proteins was observed to be remarkably similar to the sequence of the helical part of human A4-(1-40)-peptide.

Nicotine Inhibits Amyloid Formation by the β-Peptide

“…Previous NMR studies demonstrated that the -(1-28) peptide folds into an ordered R-helical structure at pH 1-4 and 7-10 in aqueous solutions containing trifluoroethanol or micelles Talafous et al, 1994). More recent NMR studies of a -(10-35)-CONH 2 fragment suggest a turn-strand-turn motif between His13 and Val24 in aqueous solution (Lee et al, 1995), while the -(1-40) peptide forms two R-helical segments between Gln15-Asp23 and Ile31-Met35 in aqueous trifluoroethanol solution (Sticht et al, 1995).…”

“…An intriguing possibility is that nicotine may prevent the R-helix f -sheet conversion, which occurs during aggregation, by binding and stabilizing the small amounts of R-helical structure that may be present for monomeric -(1-42) peptide. The three-dimensional solution structure of the -(1-28) peptide in trifluoroethanol/ water and SDS-d 25 micelle solution is predominantly R-helical (Talafous et al, 1994) and is qualitatively similar to that for the -(1-40) peptide (Sticht et al, 1995). For the present study, we followed the binding of nicotine with the -(1-28) peptide in SDS-d 25 solution at pH 7.2.…”

The Alzheimer’s β amyloid (Aβ1–39) monomer in an implicit solvent

“…32 However, cluster A deviates from the ones found in NMR experiments of A␤ in TFE/water. 16 The average main chain RMSD between cluster A structure and the 20 NMR models of the 1AML.PDB is 9.89 Å, where structural superposition is done by using sequence alignment on 1-39 residues.…”

“…Slightly higher in energy are conformations with solely a turn around Val12-Leu17 residues and suchconformers that have a helical region in the N-terminal, i.e., similar to the one observed in NMR studies done in trifluoroethanol ͑TFE͒/water solution. 16 …”

“…Ma and Nussinov 11 suggested that at high temperature fragments A␤ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and A␤ form a strand-loop-strand structure with parallel ␤ sheet, with an interior salt bridge between Asp23 and Lys28 residues as a major element of the fibril structure. On the other hand, computational studies using coarse-grained as well as atomistic atom models suggest the formation of antiparallel ␤ sheets by A␤ [16][17][18][19][20][21][22] subpeptides. 12 The relation between this antiparallel structure and the nucleation and fibril forming properties of in-register parallel structures formed by the full length A␤ and A␤ 1-42 peptides is not clear, and no simulation has so far reproduced the experimentally measured secondary structure contents for A␤ peptides.…”