Nature of the amyloid-β monomer and the monomer-oligomer equilibrium

Suman Nag, Bidyut Sarkar, Arkarup Bandyopadhyay, Bankanidhi Sahoo, Varun K A Sreenivasan, Mamata Kombrabail, Chandrakesan Muralidharan, Sudipta Maiti*

*Corresponding author for this work

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

The monomer to oligomer transition initiates the aggregation and pathogenic transformation of Alzheimer amyloid-β (Aβ) peptide. However, the monomeric state of this aggregationprone peptide has remained beyond the reach of most experimental techniques, and a quantitative understanding of this transition is yet to emerge. Here, we employ single-molecule level fluorescence tools to characterize the monomeric state and the monomer-oligomer transition at physiological concentrations in buffers mimicking the cerebrospinal fluid (CSF). Our measurements show that the monomer has a hydrodynamic radius of 0.9 ± 0.1 nm, which confirms the prediction made by some of the in silico studies. Surprisingly, at equilibrium, both Aβ40 and Aβ42 remain predominantly monomeric up to 3 μm, above which it forms large aggregates. This concentration is much higher than the estimated concentrations in the CSF of either normal or diseased brains. If Aβ oligomers are present in the CSF and are the key agents in Alzheimer pathology, as is generally believed, then these must be released in the CSF as preformed entities. Although the oligomers are thermodynamically unstable, we find that a large kinetic barrier, which is mostly entropic in origin, strongly impedes their dissociation. Thermodynamic principles therefore allow the development of a pharmacological agent that can catalytically convert metastable oligomers into nontoxic monomers.

Original languageEnglish
Pages (from-to)13827-13833
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number16
DOIs
Publication statusPublished - 22 Apr 2011
Externally publishedYes

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Nag, S., Sarkar, B., Bandyopadhyay, A., Sahoo, B., Sreenivasan, V. K. A., Kombrabail, M., ... Maiti, S. (2011). Nature of the amyloid-β monomer and the monomer-oligomer equilibrium. Journal of Biological Chemistry, 286(16), 13827-13833. https://doi.org/10.1074/jbc.M110.199885