Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies

Tiernan T O'Malley; Nur Alia Oktaviani; Dainan Zhang; Aleksey Lomakin; Brian O'Nuallain; Sara Linse; George B Benedek; Michael J Rowan; Frans A A Mulder; Dominic M Walsh

doi:10.1042/BJ20140219

Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies

Biochem J. 2014 Aug 1;461(3):413-26. doi: 10.1042/BJ20140219.

Authors

Tiernan T O'Malley, Nur Alia Oktaviani¹, Dainan Zhang², Aleksey Lomakin³, Brian O'Nuallain⁴, Sara Linse⁵, George B Benedek³, Michael J Rowan², Frans A A Mulder, Dominic M Walsh⁴

Affiliations

¹ ‡Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9749 AB Groningen, The Netherlands.
² §Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
³ ∥Department of Physics and Materials Processing Center, Massachusetts Institute of Technology, Cambridge, MA 02139, U.S.A.
⁴ *Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, U.S.A.
⁵ ¶Department of Biophysical Chemistry, Lund University, SE221 00 Lund, Sweden.

PMID: 24785004
DOI: 10.1042/BJ20140219

Abstract

Dimers of Aβ (amyloid β-protein) are believed to play an important role in Alzheimer's disease. In the absence of sufficient brain-derived dimers, we studied one of the only possible dimers that could be produced in vivo, [Aβ](DiY) (dityrosine cross-linked Aβ). For comparison, we used the Aβ monomer and a design dimer cross-linked by replacement of Ser²⁶ with cystine [AβS26C]₂. We showed that similar to monomers, unaggregated dimers lack appreciable structure and fail to alter long-term potentiation. Importantly, dimers exhibit subtly different structural propensities from monomers and each other, and can self-associate to form larger assemblies. Although [Aβ](DiY) and [AβS26C]₂ have distinct aggregation pathways, they both populate bioactive soluble assemblies for longer durations than Aβ monomers. Our results indicate that the link between Aβ dimers and Alzheimer's disease results from the ability of dimers to further assemble and form synaptotoxic assemblies that persist for long periods of time.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / chemically induced*
Alzheimer Disease / metabolism
Amino Acid Substitution
Amyloid beta-Peptides / chemistry
Amyloid beta-Peptides / genetics
Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / toxicity*
Animals
Cerebellum / drug effects*
Cerebellum / metabolism
Dimerization
Evoked Potentials / drug effects
Humans
Injections, Intraventricular
Kinetics
Long-Term Potentiation / drug effects
Male
Nerve Tissue Proteins / chemistry
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Nerve Tissue Proteins / toxicity*
Neurons / drug effects*
Neurons / metabolism
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments / chemistry
Peptide Fragments / genetics
Peptide Fragments / metabolism
Peptide Fragments / toxicity*
Protein Conformation
Protein Multimerization
Rats
Rats, Wistar
Recombinant Proteins / administration & dosage
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Recombinant Proteins / toxicity
Solubility
Synapses / drug effects*
Synapses / metabolism

Substances

Amyloid beta-Peptides
Nerve Tissue Proteins
Peptide Fragments
Recombinant Proteins
amyloid beta-protein (1-40)