title: Nature of the amyloid-beta monomer and the monomer-oligomer equilibrium.
abstract: The monomer to oligomer transition initiates the aggregation and pathogenic transformation of Alzheimer amyloid-β (Aβ) peptide. However, the monomeric state of this aggregation-prone 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 Aβ(40) and Aβ(42) 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.
authors.affiliation: Department of Chemical Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400005, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Nag
authors.forename: Bidyut
authors.initials: B
authors.lastname: Sarkar
authors.forename: Arkarup
authors.initials: A
authors.lastname: Bandyopadhyay
authors.forename: Bankanidhi
authors.initials: B
authors.lastname: Sahoo
authors.forename: Varun K A
authors.initials: VK
authors.lastname: Sreenivasan
authors.forename: Mamata
authors.initials: M
authors.lastname: Kombrabail
authors.forename: Chandrakesan
authors.initials: C
authors.lastname: Muralidharan
authors.forename: Sudipta
authors.initials: S
authors.lastname: Maiti
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016880:Anisotropy; D002021:Buffers; D002384:Catalysis; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D012235:Rhodamines / Q000737:chemistry; D013816:Thermodynamics; D014443:Tyrosine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D002021:Buffers; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D012235:Rhodamines; C538897:amyloid beta-protein (40-42); D014443:Tyrosine