Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ<sub>17−42</sub>

Zheng, Jie; Jang, Hyunbum; Ma, Buyong; Nussinov, Ruth

doi:10.1021/jp711335b

Cited by 70 publications

(68 citation statements)

References 54 publications

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“…There are no reports detailing the SEM appearance of amyloidoma. While microtubular morphology, apart from immunotactoids, has not been described in clinical cases of amyloidoma or amyloidosis examined ultrastructurally, the theoretical existence of an annular structure that may serve as an intermediary in the protein folding process leading to insoluble amyloid fibers had been postulated [10].…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural Analysis of Amyloidoma

Garcia

Abell-Aleff²,

Gamb³

et al. 2009

Ultrastructural Pathology

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Amyloidomas are localized mass-forming deposits of amyloid that occur with or without association with systemic amyloidosis. The ultrastructural findings in 3 amyloidomas from 2 autopsy patients with primary systemic AL amyloidosis are described. By transmission electron microscopy, there were randomly oriented nonbranching fibrils showing some unusual curvilinear forms and considerable variability in fibril diameter (two subsets of fibrils, one 12-14 nm and another 28-30 nm in diameter). The larger fibrils showed features of microtubule formation. Scanning electron microscopy demonstrated complex 3-dimensional tangles of fibrils. These findings add to the current ultrastructural and morphologic spectrum of paraprotein deposition disease.

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Section: Discussionmentioning

confidence: 99%

Ultrastructural Analysis of Amyloidoma

Garcia

Abell-Aleff²,

Gamb³

et al. 2009

Ultrastructural Pathology

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“…MD simulations of the oligomerization process of amyloidogenic proteins are becoming increasingly relevant [44][45][46][47]. However, an explicit atomistic description of the solvation phenomena described in the present work remains computationally very expensive, due to the very large number of participating water molecules.…”

Section: Discussionmentioning

confidence: 99%

Hydration Profiles of Amyloidogenic Molecular Structures

et al. 2008

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Hydration shells of normal proteins display regions of highly structured water as well as patches of less structured bulk-like water. Recent studies suggest that isomers with larger surface densities of patches of bulk-like water have an increased propensity to aggregate. These aggregates are toxic to the cellular environment. Hence, the early detection of these toxic deposits is of paramount medical importance. We show that various morphological states of association of such isomers can be differentiated from the normal protein background based on the characteristic partition between bulk, caged, and surface hydration water and the magnetic resonance (MR) signals of this water. We derive simple mathematical equations relating the compartmentalization of water to the local hydration fraction and the packing density of the newly formed molecular assemblies. Then, we employ these equations to predict the MR response of water constrained by protein aggregation. Our results indicate that single units and compact aggregates that contain no water between constituents induce a shift of the MR signal from normal protein background to values in the hyperintensity domain (bright spots), corresponding to bulk water. In contrast, large plaques that cage significant amounts of water between constituents are likely to generate MR responses in the hypointensity domain (dark spots), typical for strongly correlated water. The implication of these results is that amyloids can display both dark and bright spots when compared to the normal gray background tissue on MR images. In addition, our findings predict that the bright spots are more likely to correspond to amyloids in their early stage of development. The results help explain the MR contrast patterns of amyloids and suggest a new approach for identifying unusual protein aggregation related to disease.

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“…In parallel, our previous MD simulations have reported two stable doublelayer A oligomers associated by the N-terminal-N-terminal interactions via Gln15-Ala21 contacts for A 9-40 48 and Lys16-Glu22 contacts for A . 49 Recently, Miller et al 50 further confirmed the existence of double-layer A 17-42 oligomer forming a N-terminal-N-terminal interface. Thus, it appears that the N-terminal-N-terminal association observed in different structural symmetries can also contribute to A fibril formation.…”

Section: Discussionmentioning

confidence: 95%

Molecular Modeling of Two Distinct Triangular Oligomers in Amyloid β-protein

Zheng

Wang

et al. 2009

J. Phys. Chem. B

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Amyloid-beta (Abeta) peptides exhibit many distinct structural morphology at the early aggregate stage, some of which are biological relevant to the pathogenesis of Alzheimer's disease (AD). Atomic-resolution structures of the early Abeta aggregates and their conformational changes in amyloid aggregation remain elusive. Here, we perform all-atom molecular modeling and dynamics simulations to obtain two stable triangular-like Abeta structures with the lowest packing energy, one corresponding to the Tycko's model (Paravastu, A.; Leapman, R.; Yau, W.; Tycko, R. Proc. Nat. Acad. Soc. U.S.A. 2008, 105, 18349-18354) (referred to C-WT model) and the other corresponding to computational model (N-WT model). Both models have the same 3-fold symmetry but distinct beta-sheet organizations in which three Abeta hexamers pack together via either C-terminal beta-strand residues or N-terminal beta-strand residues forming distinct hydrophobic cross section. Structural and energetic comparisons of two 3-fold Abeta oligomers, coupled with structural changes upon the mutations occurring at the interacting interfaces, reveal that although hydrophobic interactions are still dominant forces, electrostatic interactions are more favorable in the N-WT model due to the formation of more and stable intersheet salt bridges, while solvation energy is more favorable in the C-WT model due to more exposed hydrophilic residues to solvent. Both models display many common features similar to other amyloid oligomers and therefore are likely to be biologically relevant.

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Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ₁₇₋₄₂

Cited by 70 publications

References 54 publications

Ultrastructural Analysis of Amyloidoma

Ultrastructural Analysis of Amyloidoma

Hydration Profiles of Amyloidogenic Molecular Structures

Molecular Modeling of Two Distinct Triangular Oligomers in Amyloid β-protein

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Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ17−42

Cited by 70 publications

References 54 publications

Ultrastructural Analysis of Amyloidoma

Ultrastructural Analysis of Amyloidoma

Hydration Profiles of Amyloidogenic Molecular Structures

Molecular Modeling of Two Distinct Triangular Oligomers in Amyloid β-protein

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Product

Resources

About

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ₁₇₋₄₂