Fiber Diffraction Data Indicate a Hollow Core for the Alzheimer's Aβ 3-Fold Symmetric Fibril

Abstract

Amyloid β protein (Aβ), the principal component of the extracellular plaques found in the brains of Alzheimer’s disease patients, forms fibrils well suited to structural study by X-ray fiber diffraction. Fiber diffraction patterns from the 40-residue form Aβ(1–40) confirm a number of features of a three-fold symmetric Aβ model from solid state NMR, but suggest that the fibrils have a hollow core, not present in the original ssNMR models. Diffraction patterns calculated from a revised hollow three-fold model with a more regular β-sheet structure are in much better agreement with the observed diffraction data than patterns calculated from the original ssNMR model. Refinement of a hollow-core model against ssNMR data led to a revised ssNMR model, similar to the fiber diffraction model.

Flexibility and Solvation of Amyloid-β Hydrophobic Core

“…It is also interesting that the effect of solvation on the dynamics persists across the entire temperature range, well beyond the point at which the bulk solvent is frozen. These results support the existence of a water-accessible cavity predicted by the recent molecular dynamics studies using the 3-fold structure (49,50) as well as with the work by McDonald et al (16) based on x-ray diffraction measurements, thus further emphasizing the role of this cavity in targeted drug design. Based on the fact that both the 3-fold and the 2-fold polymorphs show identical dynamics on s-ms time scale as well as identical hydration dependence, our experiments support the notion that the Met-35 contacts defining the cavity are along the fibril axis rather than across the axis, in agreement to what has been proposed based on the molecular dynamics studies (49).…”

“…The deposits (plaques) are an active subject of investigation in many research centers in an attempt to design preventative and therapeutic approaches to the disease (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The molecular structures and morphologies of the fibrils comprising the plaques have been studied at various levels with a variety of imaging and spectroscopic techniques including neutron diffraction, atomic force microscopy, cryoelectronmicroscopy,magneticresonancespectroscopy,andfluorescence (8,(11)(12)(13)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…The flexibility of non-core regions has been shown by multiple techniques such as nuclear magnetic resonance (9,24,25,(41)(42)(43), electron paramagnetic resonance, (28) hydrogendeuterium exchange probed by mass-spectrometry (44 -46), and x-ray crystallography (47). Based on x-ray, cryo-EM studies (16,48), and molecular dynamics simulations (49,50), it has also been suggested that some of the polymorphs can have a hollow hydrophobic core cavity that can be relatively wateraccessible. A recent study based on solid-state NMR and modeling has also explored the role of cavities in the interaction between A␤ and a non-steroidal anti-inflammatory drug (51,52).…”

On the lack of polymorphism in Aβ‐peptide aggregates derived from patient brains

“…17 The resulting interior channels are water-accessible. 13,30 This can be seen in a snapshot from an equilibrated part of the simulation (5 ns of simulation) where water molecules enter into the interior channel (Fig. 6).…”

Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure

“…1A, B), and even the relatively small Alzheimer's-associated Ab peptide has a U-shaped 2-b-strand architecture. 8,9 These are cross-b structures, and they are amyloids, but they are qualitatively more complex than simple stacked sheets. Generic stacked-sheet amyloid structures do not appear to share the self-propagating character of structurally more complex prions.…”