Journal of Alzheimer's Disease, volume 63, issue 2, pages 539-550

Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides

Радько С. П. ^{1, 2}

Хмелёва С. А. ²

Mantsyzov Alexey B. ³

Kiseleva Yana Y. ²

Митькевич В. А. ¹

Козин С. А. ¹

A. MAKAROV Alexander ¹

Hide authors affiliations Show authors affiliations: 3 affiliations

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia |

Orekhovich Institute of Biomedical Chemistry, Moscow, Russia |

Faculty of fundamental medicine, Lomonosov Moscow State University, Moscow, Russia |

Publication type: Journal Article

Publication date: 2018-04-06

IOS Press

Journal: Journal of Alzheimer's Disease

Quartile SCImago

Quartile WOS

Impact factor: 4

ISSN: 13872877, 18758908

DOI: 10.3233/JAD-171120

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General Medicine

Clinical Psychology

Psychiatry and Mental health

General Neuroscience

Geriatrics and Gerontology

Abstract

Zinc-induced aggregation of amyloid-β peptides (Aβ) is considered to contribute to the pathogenesis of Alzheimer's disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Aβ self-aggregation in vitro, the impact of GAGs on the formation of zinc-induced amorphous Aβ aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Aβ42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Aβ16 peptides to model the Aβ metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Aβ42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Aβ42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Aβ42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Aβ16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Aβ aggregation.

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Citations by journals

	1
Pharmacological Reviews	Pharmacological Reviews, 1, 11.11% Pharmacological Reviews 1 publication, 11.11%
Polymers	Polymers, 1, 11.11% Polymers 1 publication, 11.11%
Biomolecules	Biomolecules, 1, 11.11% Biomolecules 1 publication, 11.11%
Pharmaceutics	Pharmaceutics, 1, 11.11% Pharmaceutics 1 publication, 11.11%
Colloid and Polymer Science	Colloid and Polymer Science, 1, 11.11% Colloid and Polymer Science 1 publication, 11.11%
Nature Communications	Nature Communications, 1, 11.11% Nature Communications 1 publication, 11.11%
Molecular Biology	Molecular Biology, 1, 11.11% Molecular Biology 1 publication, 11.11%
Current Computer-Aided Drug Design	Current Computer-Aided Drug Design, 1, 11.11% Current Computer-Aided Drug Design 1 publication, 11.11%
	1

Citations by publishers

	1 2 3
Multidisciplinary Digital Publishing Institute (MDPI)	Multidisciplinary Digital Publishing Institute (MDPI), 3, 33.33% Multidisciplinary Digital Publishing Institute (MDPI) 3 publications, 33.33%
Springer Nature	Springer Nature, 2, 22.22% Springer Nature 2 publications, 22.22%
American Society for Pharmacology and Experimental Therapeutics	American Society for Pharmacology and Experimental Therapeutics, 1, 11.11% American Society for Pharmacology and Experimental Therapeutics 1 publication, 11.11%
Pleiades Publishing	Pleiades Publishing, 1, 11.11% Pleiades Publishing 1 publication, 11.11%
Bentham Science	Bentham Science, 1, 11.11% Bentham Science 1 publication, 11.11%
	1 2 3

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Радько С. П. et al. Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides // Journal of Alzheimer's Disease. 2018. Vol. 63. No. 2. pp. 539-550.

GOST all authors (up to 50) Copy

Радько С. П., Хмелёва С. А., Mantsyzov A. B., Kiseleva Y. Y., Митькевич В. А., Козин С. А., A. MAKAROV A. Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides // Journal of Alzheimer's Disease. 2018. Vol. 63. No. 2. pp. 539-550.

RIS |

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RIS Copy

TY - JOUR

DO - 10.3233/JAD-171120

UR - https://doi.org/10.3233%2FJAD-171120

TI - Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides

T2 - Journal of Alzheimer's Disease

AU - Kiseleva, Yana Y.

AU - Радько, С. П.

AU - Хмелёва, С. А.

AU - Mantsyzov, Alexey B.

AU - Митькевич, В. А.

AU - Козин, С. А.

AU - A. MAKAROV, Alexander

PY - 2018

DA - 2018/04/06 00:00:00

PB - IOS Press

SP - 539-550

IS - 2

VL - 63

SN - 1387-2877

SN - 1875-8908

ER -

BibTex |

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@article{2018_Радько,

author = {Yana Y. Kiseleva and С. П. Радько and С. А. Хмелёва and Alexey B. Mantsyzov and В. А. Митькевич and С. А. Козин and Alexander A. MAKAROV},

title = {Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides},

journal = {Journal of Alzheimer's Disease},

year = {2018},

volume = {63},

publisher = {IOS Press},

month = {apr},

url = {https://doi.org/10.3233%2FJAD-171120},

number = {2},

pages = {539--550},

doi = {10.3233/JAD-171120}

}

MLA

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Радько, С. П., et al. “Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides.” Journal of Alzheimer's Disease, vol. 63, no. 2, Apr. 2018, pp. 539-550. https://doi.org/10.3233%2FJAD-171120.

Found error?

Publisher

IOS Press

Journal

Journal of Alzheimer's Disease

Quartile SCImago

Quartile WOS

Impact factor

ISSN

13872877 (Print)
18758908 (Electronic)

Profiles

Mantsyzov, Alexey B