Molecular structures of quiescently grown and brain-derived polymorphic fibrils of the Alzheimer amyloid Aβ_9-40 peptide: A comparison to agitated fibrils

TY - JOUR

T1 - Molecular structures of quiescently grown and brain-derived polymorphic fibrils of the Alzheimer amyloid Aβ9-40 peptide

T2 - A comparison to agitated fibrils

AU - Wu, Chun

AU - Bowers, Michael T.

AU - Shea, Joan Emma

PY - 2010/3

Y1 - 2010/3

N2 - 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 Aβb 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.

AB - 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 Aβb 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.

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U2 - 10.1371/journal.pcbi.1000693

DO - 10.1371/journal.pcbi.1000693

M3 - Article

C2 - 20221247

SN - 1553-734X

VL - 6

JO - PLoS computational biology

JF - PLoS computational biology

IS - 3

ER -