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Daniel Otzen

An Aß concatemer with altered aggregation propensities

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An Aß concatemer with altered aggregation propensities. / Giehm, L; Dal Degan, F; Fraser, P; Klysner, S; Otzen, Daniel E.

In: BBA General Subjects, Vol. 1804, No. 10, 01.10.2010, p. 2025-35.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Giehm, L, Dal Degan, F, Fraser, P, Klysner, S & Otzen, DE 2010, 'An Aß concatemer with altered aggregation propensities', BBA General Subjects, vol. 1804, no. 10, pp. 2025-35. https://doi.org/10.1016/j.bbapap.2010.06.023

APA

Giehm, L., Dal Degan, F., Fraser, P., Klysner, S., & Otzen, D. E. (2010). An Aß concatemer with altered aggregation propensities. BBA General Subjects, 1804(10), 2025-35. https://doi.org/10.1016/j.bbapap.2010.06.023

CBE

Giehm L, Dal Degan F, Fraser P, Klysner S, Otzen DE. 2010. An Aß concatemer with altered aggregation propensities. BBA General Subjects. 1804(10):2025-35. https://doi.org/10.1016/j.bbapap.2010.06.023

MLA

Vancouver

Giehm L, Dal Degan F, Fraser P, Klysner S, Otzen DE. An Aß concatemer with altered aggregation propensities. BBA General Subjects. 2010 Oct 1;1804(10):2025-35. https://doi.org/10.1016/j.bbapap.2010.06.023

Author

Giehm, L ; Dal Degan, F ; Fraser, P ; Klysner, S ; Otzen, Daniel E. / An Aß concatemer with altered aggregation propensities. In: BBA General Subjects. 2010 ; Vol. 1804, No. 10. pp. 2025-35.

Bibtex

@article{d2b66bcd69f94307aab0bcecf49d20f8,
title = "An A{\ss} concatemer with altered aggregation propensities",
abstract = "We present an analysis of the conformational and aggregative properties of an A{\ss} concatemer (Con-Alz) of interest for vaccine development against Alzheimer's disease. Con-Alz consists of 3 copies of the 43 residues of the A{\ss} peptide separated by the P2 and P30 T-cell epitopes from the tetanus toxin. Even in the presence of high concentrations of denaturants or fluorinated alcohols, Con-Alz has a very high propensity to form aggregates which slowly coalesce over time with changes in secondary, tertiary and quaternary structure. Only micellar concentrations of SDS were able to inhibit aggregation. The increase in the ability to bind the fibril-binding dye ThT increases without lag time, which is characteristic of relatively amorphous aggregates. Confirming this, electron microscopy reveals that Con-Alz adopts a morphology resembling truncated protofibrils after prolonged incubation, but it is unable to assemble into classical amyloid fibrils. Despite its high propensity to aggregate, Con-Alz does not show any significant ability to permeabilize vesicles, which for fibrillating proteins is taken to be a key factor in aggregate cytotoxicity and is attributed to oligomers formed at an early stage in the fibrillation process. Physically linking multiple copies of the A{\ss}-peptide may thus sterically restrict Con-Alz against forming cytotoxic oligomers, forcing it instead to adopt a less well-organized assembly of intermeshed polypeptide chains.",
keywords = "Alzheimer Disease, Amino Acid Sequence, Amyloid, Amyloid beta-Peptides, Circular Dichroism, Humans, Models, Molecular, Molecular Sequence Data, Peptide Fragments, Protein Conformation, Protein Multimerization",
author = "L Giehm and {Dal Degan}, F and P Fraser and S Klysner and Otzen, {Daniel E}",
note = "Copyright {\textcopyright} 2010 Elsevier B.V. All rights reserved.",
year = "2010",
month = oct,
day = "1",
doi = "10.1016/j.bbapap.2010.06.023",
language = "English",
volume = "1804",
pages = "2025--35",
journal = "B B A - General Subjects",
issn = "0304-4165",
publisher = "Elsevier BV",
number = "10",

}

RIS

TY - JOUR

T1 - An Aß concatemer with altered aggregation propensities

AU - Giehm, L

AU - Dal Degan, F

AU - Fraser, P

AU - Klysner, S

AU - Otzen, Daniel E

N1 - Copyright © 2010 Elsevier B.V. All rights reserved.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - We present an analysis of the conformational and aggregative properties of an Aß concatemer (Con-Alz) of interest for vaccine development against Alzheimer's disease. Con-Alz consists of 3 copies of the 43 residues of the Aß peptide separated by the P2 and P30 T-cell epitopes from the tetanus toxin. Even in the presence of high concentrations of denaturants or fluorinated alcohols, Con-Alz has a very high propensity to form aggregates which slowly coalesce over time with changes in secondary, tertiary and quaternary structure. Only micellar concentrations of SDS were able to inhibit aggregation. The increase in the ability to bind the fibril-binding dye ThT increases without lag time, which is characteristic of relatively amorphous aggregates. Confirming this, electron microscopy reveals that Con-Alz adopts a morphology resembling truncated protofibrils after prolonged incubation, but it is unable to assemble into classical amyloid fibrils. Despite its high propensity to aggregate, Con-Alz does not show any significant ability to permeabilize vesicles, which for fibrillating proteins is taken to be a key factor in aggregate cytotoxicity and is attributed to oligomers formed at an early stage in the fibrillation process. Physically linking multiple copies of the Aß-peptide may thus sterically restrict Con-Alz against forming cytotoxic oligomers, forcing it instead to adopt a less well-organized assembly of intermeshed polypeptide chains.

AB - We present an analysis of the conformational and aggregative properties of an Aß concatemer (Con-Alz) of interest for vaccine development against Alzheimer's disease. Con-Alz consists of 3 copies of the 43 residues of the Aß peptide separated by the P2 and P30 T-cell epitopes from the tetanus toxin. Even in the presence of high concentrations of denaturants or fluorinated alcohols, Con-Alz has a very high propensity to form aggregates which slowly coalesce over time with changes in secondary, tertiary and quaternary structure. Only micellar concentrations of SDS were able to inhibit aggregation. The increase in the ability to bind the fibril-binding dye ThT increases without lag time, which is characteristic of relatively amorphous aggregates. Confirming this, electron microscopy reveals that Con-Alz adopts a morphology resembling truncated protofibrils after prolonged incubation, but it is unable to assemble into classical amyloid fibrils. Despite its high propensity to aggregate, Con-Alz does not show any significant ability to permeabilize vesicles, which for fibrillating proteins is taken to be a key factor in aggregate cytotoxicity and is attributed to oligomers formed at an early stage in the fibrillation process. Physically linking multiple copies of the Aß-peptide may thus sterically restrict Con-Alz against forming cytotoxic oligomers, forcing it instead to adopt a less well-organized assembly of intermeshed polypeptide chains.

KW - Alzheimer Disease

KW - Amino Acid Sequence

KW - Amyloid

KW - Amyloid beta-Peptides

KW - Circular Dichroism

KW - Humans

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Peptide Fragments

KW - Protein Conformation

KW - Protein Multimerization

U2 - 10.1016/j.bbapap.2010.06.023

DO - 10.1016/j.bbapap.2010.06.023

M3 - Journal article

C2 - 20619363

VL - 1804

SP - 2025

EP - 2035

JO - B B A - General Subjects

JF - B B A - General Subjects

SN - 0304-4165

IS - 10

ER -