Molecular Structures of Quiescently Grown and Brain-Derived Polymorphic Fibrils of the Alzheimer Amyloid Aβ9-40 Peptide: A Comparison to Agitated Fibrils

The presence of amyloid deposits consisting primarily of Amyloid-β (Aβ) fibril in the brain is a hallmark of Alzheimer's disease (AD). The morphologies of these fibrils are exquisitely sensitive to environmental conditions. Using molecular dynamics simulations combined with data from previously published solid-state NMR experiments, we propose the first atomically detailed structures of two asymmetric polymorphs of the Aβ9-40 peptide fibril. The first corresponds to synthetic fibrils grown under quiescent conditions and the second to fibrils derived from AD patients' brain-extracts. Our core structure in both fibril structures consists of a layered structure in which three cross-β subunits are arranged in six tightly stacked β-sheet layers with an antiparallel hydrophobic-hydrophobic and an antiparallel polar-polar interface. The synthetic and brain-derived structures differ primarily in the side-chain orientation of one β-strand. The presence of a large and continually exposed hydrophobic surface (buried in the symmetric agitated Aβ fibrils) may account for the higher toxicity of the asymmetric fibrils. Our model explains the effects of external perturbations on the fibril lateral architecture as well as the fibrillogenesis inhibiting action of amphiphilic molecules.Author Summary: Amyloid diseases are characterized by the presence of amyloid fibrils on organs and tissue in the body. Alzheimer's disease, Parkinson's diseases and Type II Diabetes are all examples of amyloid diseases. Determining the structure of amyloid fibrils is critical for understanding the mechanism of fibril formation as well as for the design of inhibitor molecules that can prevent aggregation. In the case of the Alzheimer Amyloid-β (Aβ) peptide, the structure of fibrils grown under conditions of mechanical agitation has been elucidated from a combination of simulation and experiments. However, the structures of the asymmetric quiescent Aβ fibrils (grown under conditions akin to physiological conditions) and of Alzheimer's brain–derived fibrils are not known. In this paper, we propose the first atomically detailed structures of these two fibrils, using molecular dynamics simulations combined with data from previously published experiments. In additions, we suggest a unifying lateral growth mechanism that explains the increased toxicity of quiescent Aβ fibrils, the effects of external perturbations on fibril lateral architecture and the inhibition mechanism of the small molecule inhibitors on fibril formation.