Molecular basis for amyloid-beta polymorphism

Abstract

Amyloid-beta (Aβ) aggregates are the main constituent of senile plaques, the histological hallmark of Alzheimer's disease. Aβ molecules form β-sheet containing structures that assemble into a variety of polymorphic oligomers, protofibers, and fibers that exhibit a range of lifetimes and cellular toxicities. This polymorphic nature of Aβ has frustrated its biophysical characterization, its structural determination, and our understanding of its pathological mechanism. To elucidate Aβ polymorphism in atomic detail, we determined eight new microcrystal structures of fiber-forming segments of Aβ. These structures, all of short, self-complementing pairs of β-sheets termed steric zippers, reveal a variety of modes of self-association of Aβ. Combining these atomic structures with previous NMR studies allows us to propose several fiber models, offering molecular models for some of the repertoire of polydisperse structures accessible to Aβ. These structures and molecular models contribute fundamental information for understanding Aβ polymorphic nature and pathogenesis.

Fig. 1.

Amyloidogenic propensity of Aβ homotypic and heterotypic interactions predicted by the 3D-profile method. (A) The 3D-profile method calculates the RosettaDesign energy (58) for the self-association (homotypic interactions) of six amino acid peptide segments (41, 59). The histogram of peptide segments is colored in rainbow from blue to red for segments with low-to-high predicted amyloid propensity. The Aβ amino acid sequence and residue numbering are shown (Top). (B) Aβ segments whose crystal structures have been determined are shown as arrows; blue and purple code for structures presented here or in a previous publication (45), respectively. (C) The 3D-profile method prediction for the association of hetero- and homo-Aβ segments is presented on a 2D-interaction heat map colored as in A. Each element represents the interaction energy of the hypothetical steric zipper of six residues that starts at the residues at the corresponding positions on the axes. Three main cross-peaks predicting high fiber-formation propensity are boxed.

Fig. 2.

Crystal structures of Aβ segments, shown in projection down the fiber axes. The Aβ segments are packed as pairs of interdigitated β-sheets, generally with a dry interface between them, termed steric zippers, forming the basic unit of the fiber (44, 45). The view here looks down the fiber axis, showing only four layers of β-strands in each β-sheet; actual fibers can contain more than 100,000 layers. Each panel is labeled with the amino acid sequence of each segment and the starting and ending residue numbers. Molecules are shown as sticks with noncarbon atoms colored by atom type. In structures with β-sheets composed of parallel strands (D, F, G, and K), the carbons are in white. Antiparallel strands forming β-sheet structures (A–C, E, H–J) are alternately colored with carbons colored white and blue. Closest partners across the dry interface share the same color. Some of the panels are split in two halves; each half represents a different dry interface within the same crystal structure.

Fig. 3.

Models of protofilament associations. The crystal structure of Aβ35-42 Form II was used to model interactions between two protofilaments. The protofilament structure is derived from experiment-based models of Aβ1-40 (residues 1–9 are disordered in the fiber) (34) (Upper) or Aβ1-42 (residues 1–17 are disordered in the fiber) (19) (Lower). See also Figs. S4–S6 for other models of Aβ polymorphs based on the structures of Fig. 2.