Molecular basis for amyloid-β 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.amyloid aggregation | 3D profile | protofilaments | heterotypic zipper

Cryo-EM reveals the steric zipper structure of a light chain-derived amyloid fibril

“…Face-to-face packed dimers are also present in other types of amyloid-like fibrils formed by Alzheimer's Aβ (1-40) and Aβ (1-42) peptide and may point to an assembly pathway that starts with the formation of dimers (7,9). Although steric zippers are likely also present in Aβ fibrils (17), they describe only the interaction between small segments of the Aβ peptide, making a full description of principles of fibril formation more difficult. In the case of the AL1 peptide fibril we imaged here, the steric zipper extends along most of the peptide dimer interface, making it the predominant structural feature.…”

“…Microcrystals usually comprised untwisted β-sheets (14,15), whereas β-sheets were characteristically twisted in fibrils (7)(8)(9)(10)(11)(20)(21)(22). Finally, even in those cases where a zipper was implicated in the structure of a fibril, it included only a relatively small portion of the fibril cross-β structure (16,17). Hence, steric zippers explained only a minor fraction of the interactions stabilizing these fibrils.…”

“…Steric zippers represent pairs of self-complementary β-sheets that are formed by very short peptides (14,15). Although zippers were suggested to constitute the structural spines of amyloid fibrils formed from usually much longer polypeptide chains (16,17), their role for fibril formation remains controversial. For example, solid-state NMR data suggest that the peptide conformations in fibrils and microcrystals differ even when formed from the same peptide (18).…”

The Three-Dimensional Structures of Amyloids

“…This notion is further strengthened by the high-resolution X-ray crystallography studies of short amyloid peptides that form different microcrystals comprising different classes of steric zippers. For example, the fragment of Ab comprising residues 35-42 crystallized in two forms with both parallel and antiparallel b-sheet stacking, as shown in Figure 4 ( Colletier et al 2011). …”

“…For example, for Ab(1-42), among others, the segments 16-21, 27-32, or 35-42 all individually form an amyloid (Fig. 4) (Colletier et al 2011), and each of these segments individually may be part of the core of the amyloid.…”