Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease βA4 peptides

Hilbich, Caroline; Kisters‐Woike, Brigitte; Reed, Jennifer; Masters, Colin L.; Beyreuther, Konrad

doi:10.1016/0022-2836(92)90835-8

Cited by 411 publications

(369 citation statements)

References 20 publications

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“…This ranking matches the local hydrophobicity of the A␤ sequence at the modification site: K16 resides in the most hydrophobic context (…VHHQKLVFF…), followed by K28 (…VGSNKGAII…), and then D1 (DAEFRHDSG…). This correlation between local hydrophobicity and the kinetic effect of metabolite modification suggests that K16 and its surrounding residues were already important for aggregate nucleation and growth, consistent with previous findings (39), and that the increase in hydrophobicity attendant to the attachment of 1(2) to K16 magnifies the influence of this region. Thus, it is a hotspot for hydrophobic metabolite modification-mediated aggregation.…”

Section: Discussionsupporting

confidence: 89%

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

Usui

Hulleman

Paulsson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of amyloid ␤-peptide (A␤) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between A␤ and the aldehyde-bearing cholesterol oxidation product 3-␤-hydroxy-5-oxo-5,6-secocholestan-6-al is known to increase A␤ amyloidogenicity. Here, we synthesized A␤ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified A␤ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from A␤ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified A␤ under identical conditions and at the same concentration. Our results show that A␤ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of A␤.A␤ ͉ amyloid ͉ oxidative stress ͉ oxidized metabolite ͉ protein misfolding

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Section: Discussionsupporting

confidence: 89%

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

Usui

Hulleman

Paulsson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…6 We also know that the ThT signal, normalized for constant fibril weight, can differ for the amyloid fibrils of different point mutants of A␤ over a 6-fold range. 5 The 2-fold difference between the ThT signals in Fig. 5 for the two A␤ elongation reactions that have reached equilibrium (E, Ⅺ) suggest that the structures of these A␤ fibrils are substantially different, presumably influenced by the nature of the seed.…”

Section: Discussionmentioning

confidence: 98%

“…This is relevant to the work described here, since we attempt to draw biological conclusions from studies of such artificial fibrils. We think it is justified to do this, since amyloid deposits in authentic disease tissue from both Alzheimer's disease (38) and Huntington's disease brains 5 are capable of carrying out elongation reactions in vitro when provided with appropriate monomeric building blocks. At the same time, amyloid fibrils grown in vitro may not be identical in structure and/or function to naturally derived amyloid in some other respects.…”

Section: Discussionmentioning

confidence: 99%

Seeding Specificity in Amyloid Growth Induced by Heterologous Fibrils

O’Nuallain

Williams

Westermark

et al. 2004

Journal of Biological Chemistry

385

437

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Over residues 15-36, which comprise the H-bonded core of the amyloid fibrils it forms, the Alzheimer's disease plaque peptide amyloid ␤ (A␤) possesses a very similar sequence to that of another short, amyloidogenic peptide, islet amyloid polypeptide (IAPP). Using elongation rates to quantify seeding efficiency, we inquired into the relationship between primary sequence similarity and seeding efficiency between A␤-(1-40) and amyloid fibrils produced from IAPP as well as other proteins. In both a solution phase and a microtiter plate elongation assay, IAPP fibrils are poor seeds for A␤-(1-40) elongation, exhibiting weight-normalized efficiencies of only 1-2% compared with A␤-(1-40) fibrils. Amyloid fibrils of peptides with sequences completely unrelated to A␤ also exhibit poor to negligible seeding ability for A␤ elongation. Fibrils from a number of point mutants of A␤-(1-40) exhibit intermediate seeding abilities for wild-type A␤ elongation, with differing efficiencies depending on whether or not the mutation is in the amyloid core region. The results suggest that amyloid fibrils from different proteins exhibit structural differences that control seeding efficiencies. Preliminary results also suggest that identical sequences can grow into different conformations of amyloid fibrils as detected by seeding efficiencies. The results have a number of implications for amyloid structure and biology.

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“…Amyloid fibrillization is generally considered to be driven by hydrophobic rather than electrostatic interactions (34,(41)(42)(43). A␤ contains central (residues 17-21) and C-terminal (residues 30-40) hydrophobic segments.…”

Section: Discussionmentioning

confidence: 99%

A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR

Petkova

Ishii

Balbach

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

1,765

188

2,350

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We present a structural model for amyloid fibrils formed by the 40-residue ␤-amyloid peptide associated with Alzheimer's disease (A␤ 1-40), based on a set of experimental constraints from solid state NMR spectroscopy. The model additionally incorporates the cross-␤ structural motif established by x-ray fiber diffraction and satisfies constraints on A␤ 1-40 fibril dimensions and mass-per-length determined from electron microscopy. Approximately the first 10 residues of A␤ 1-40 are structurally disordered in the fibrils. Residues 12-24 and 30 -40 adopt ␤-strand conformations and form parallel ␤-sheets through intermolecular hydrogen bonding. Residues 25-29 contain a bend of the peptide backbone that brings the two ␤-sheets in contact through sidechain-sidechain interactions. A single cross-␤ unit is then a double-layered ␤-sheet structure with a hydrophobic core and one hydrophobic face. The only charged sidechains in the core are those of D23 and K28, which form salt bridges. Fibrils with minimum mass-per-length and diameter consist of two cross-␤ units with their hydrophobic faces juxtaposed.A myloid fibrils are filamentous structures, with typical diameters of Ϸ10 nm and lengths up to several micrometers, formed by numerous peptides and proteins with disparate sequences and molecular weights. Biomedical interest in amyloid fibrils arises from their occurrence in amyloid diseases (1), including Alzheimer's disease, type 2 diabetes, Huntington's disease, and prion diseases. Current interest in the molecular structures of amyloid fibrils additionally arises from fundamental questions regarding the molecular mechanism of amyloid formation and the nature of the intermolecular interactions that stabilize these structures for an extremely diverse class of polypeptides.No high-resolution molecular structure of an amyloid fibril has yet been determined experimentally because amyloid fibrils are noncrystalline solid materials and are therefore incompatible with x-ray crystallography and liquid state NMR. X-ray fiber diffraction shows that amyloid fibrils contain cross-␤ structural motifs, i.e., extended ␤-sheets in which the ␤-strand segments run approximately perpendicular to, and the intermolecular hydrogen bonds run approximately parallel to, the long axis of the fibril (2, 3). Other molecular-level structural features of amyloid fibrils are not well established.In the case of fibrils formed by the full-length ␤-amyloid peptide associated with Alzheimer's disease (A␤), which ranges from 39 to 43 residues in length in vivo (4, 5), several molecular models have been proposed (6-10). These models exhibit many qualitative and quantitative differences, reflecting the paucity of experimental constraints. All of these models are inconsistent with recent measurements of 13 C-13 C nuclear magnetic dipole-dipole couplings (i.e., intermolecular distances) by solid state NMR (11-13), which imply an in-register parallel alignment of peptide chains within the cross-␤ motif in A␤ 1-40 and A␤ 1-42 fibrils (A␤ mϪn denotes residues m t...

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Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease βA4 peptides

Cited by 411 publications

References 20 publications

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

Seeding Specificity in Amyloid Growth Induced by Heterologous Fibrils

A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR

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