Context dependence of protein misfolding and structural strains in neurodegenerative diseases

Abstract

Vast arrays of structural forms are accessible to simple amyloid peptides and environmental conditions can direct assembly into single phases. These insights are now being applied to the aggregation of the Aβ peptide of Alzheimer's disease and the identification of causative phases. We extend use of the imaging agent Pittsburgh compound B to discriminate among Aβ phases and begin to define conditions of relevance to the disease state. Also, we specifically highlight the development of methods for defining the structures of these more complex phases.

Keywords: NMR spectrsocopy; PIB; amyloid; amyloid strains; nanotubes.

Figure 1

(A) Pittsburgh Compound B (PiB), X=H and [¹⁹F] PiB (X=F). Transmission electron microscopy (TEM) micrographs of Aβ(1–40) assembled (B) quiescently, or (C) with constant agitation. (D) [³H]PiB binding to Aβ fibers assembled under quiescent (Q) or agitated (Ag) conditions.

Figure 2

N-acetyl Aβ(16–22) peptide bilayer of anti-parallel β-sheets places lysine residues (colored blue) at both ends of each leaflet with TFA ions trapped within the peptide bilayer interface. Expansion shows 6 laminated β-sheets, viewed down the H-bonding axis, with alanine – valine cross-strand pairing within each β-sheet. Peptide is drawn as sticks with lysines colored blue and the remaining amino acids colored grey or white to highlight the two leaflets. TFA anions are shown as spheres with green fluorines, gray carbons and red oxygens.

Figure 3

Aβ(1–42) assembled in the presence of lipid brain extract. (A) TEM micrographs of the co-assembly after 7 days, showing fibers (arrowhead) and vesicles (arrow with tail). ¹³C{¹⁵N}REDOR (B) full-echo (S₀) spectrum and (C) dephasing for [1-¹³C]L34[¹⁵N]V36 Aβ42 assembled in lipid brain extracts. The i to i+2 ¹³CO-¹⁵N idealized distance for the α-helix is 3.3 Å, for an anti-parallel β-sheet is 4.4 Å, and for a parallel β-sheet is 4 Å.

Figure 4

Molecular model of N-lauroyl Aβ(16–22) showing (A) positions of ¹³CH₃, [¹⁵N] Leu17 and Val18 and with distances consistent with ¹³C{¹⁵N}REDOR measurements places the ω-CH₃ of the lauroyl chain closer to the middle of the peptide than the ends. High-resolution SEM and resulting models for (B) N-acetyl and (C) N-lauroyl Aβ(16–22) highlight the position of the lauroyl chain with the increased laminate distance.