Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril

Abstract

Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1–40) and Aβ(1–42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1–42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer’s disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1–42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15–42 forming a double-horseshoe–like cross–β-sheet entity with maximally buried hydrophobic side chains. Residues 1–14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.

Mammalian amyloidogenic proteins promote prion nucleation in yeast

“…Notably, the triple mutation F19S, F20S, I31P entirely abolished [PSI + ] nucleation by both Sup35N-Aβ1-42 ( Fig 5D, Table 1) and Sup35NM-Aβ1-42 ( Table 1). The K to E substitution, affecting the β3 strand and disrupting a presumable "salt bridge" that involves position K28 (e. g. [44,50], also significantly decreased [PSI + ] nucleation by Sup35N-Aβ1-42 in yeast (Fig 5E). In contrast, the substitution D23N, a so-called "Iowa mutation" associated with the heritable form of AD [11,13], significantly increased [PSI + ] nucleation in yeast ( Fig 5F).…”

“…Several variants of Aβ peptide exist in humans, of which Aβ1-42 and Aβ1-40 (lacking the last two amino acid residues) are the most abundant ones [41]. Of these two, Aβ1-42 is considered to be the most amyloidogenic and most pathogenic form in humans [30,42] Nucleation of a yeast prion by mammalian proteins structural models placing the N-terminal region of Aβ outside of amyloid core [43,44].…”

“…Previous in vitro experiments and structural data identified positions 19, 20 and 31 as being important for amyloid formation by Aβ [45,46,47] and located within intramolecular cross-β sheets of Aβ1-40 polymers [48,49]. However, according to the most recent structural model of Aβ1-42 polymers (e. g., [44]), only position 31 is located within one of the β-strands, while positions 19 and 20 are involved in hydrophobic interactions. Indeed, the substitution I31P, breaking the proposed β4-strand, greatly decreased [PSI + ] nucleation by Sup35N-Aβ42, while the substitution F19S caused only a mild decrease, and the substitution F20S had almost no effect ( Fig 5D).…”

“…This peptide is drastically inefficient in prion nucleation in the yeast assay, compared to the highly amyloidogenic and presumably pathogenic Aβ42 (Fig 5A). While previous structural studies used the in vitro produced Aβ40 polymers [48,49] the high resolution structures of Aβ42 amyloids, mostly based on solid state NMR have also been reported recently [43,44,50]. These structures include two molecules per polymer unit, and five β intermolecular sheets spanning residues 2-6 (β1), 15-18 (β2), 26-28 (β3), 30-32 (β4), and 39-42 (β5) per each "half" of the fibril.…”

Investigating Amyloid β toxicity in Drosophila melanogaste

“…There are several different models of Aβ oligomer/fibril structure, with a general agreement on a hidden hydrophobic C-terminal sequence (30-40/42) and central region (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), with a partially accessible hydrophilic N-terminal region (1-10/12) [122]- [126]. All models presume that the hidden C-terminal and central regions make up β-strands, forming extensive hydrogen interactions between the hydrophobic side chains of adjacent peptides.…”